Spinal cord injury (SCI) causes the irreversible loss of spinal cord parenchyma including astroglia, oligodendroglia and neurons. In particular, severe injuries can lead to an almost complete neural cell loss at the lesion site and structural and functional recovery might only be accomplished by appropriate cell and tissue replacement. Stem cells have the capacity to differentiate into all relevant neural cell types necessary to replace degenerated spinal cord tissue and can now be obtained from virtually any stage of development. Within the last two decades, many in vivo studies in small animal models of SCI have demonstrated that stem cell transplantation can promote morphological and, in some cases, functional recovery via various mechanisms including remyelination, axon growth and regeneration, or neuronal replacement. However, only two well-documented neural-stem-cell-based transplantation strategies have moved to phase I clinical trials to date. This review aims to provide an overview about the current status of preclinical and clinical neural stem cell transplantation and discusses future perspectives in the field.

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This article is about the medical therapy. For the cell type, see Stem cell.

Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition.

Bone marrow transplant is the most widely used stem-cell therapy, but some therapies derived from umbilical cord blood are also in use. Research is underway to develop various sources for stem cells, and to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes, heart disease, and other conditions.

Stem-cell therapy has become controversial following developments such as the ability of scientists to isolate and culture embryonic stem cells, to create stem cells using somatic cell nuclear transfer and their use of techniques to create induced pluripotent stem cells. This controversy is often related to abortion politics and to human cloning. Additionally, efforts to market treatments based on transplant of stored umbilical cord blood have been controversial.

For over 30 years, bone marrow has been used to treat cancer patients with conditions such as leukaemia and lymphoma; this is the only form of stem-cell therapy that is widely practiced.[1][2][3] During chemotherapy, most growing cells are killed by the cytotoxic agents. These agents, however, cannot discriminate between the leukaemia or neoplastic cells, and the hematopoietic stem cells within the bone marrow. It is this side effect of conventional chemotherapy strategies that the stem-cell transplant attempts to reverse; a donor's healthy bone marrow reintroduces functional stem cells to replace the cells lost in the host's body during treatment. The transplanted cells also generate an immune response that helps to kill off the cancer cells; this process can go too far, however, leading to graft vs host disease, the most serious side effect of this treatment.[4]

Another stem-cell therapy called Prochymal, was conditionally approved in Canada in 2012 for the management of acute graft-vs-host disease in children who are unresponsive to steroids.[5] It is an allogenic stem therapy based on mesenchymal stem cells (MSCs) derived from the bone marrow of adult donors. MSCs are purified from the marrow, cultured and packaged, with up to 10,000 doses derived from a single donor. The doses are stored frozen until needed.[6]

The FDA has approved five hematopoietic stem-cell products derived from umbilical cord blood, for the treatment of blood and immunological diseases.[7]

In 2014, the European Medicines Agency recommended approval of Holoclar, a treatment involving stem cells, for use in the European Union. Holoclar is used for people with severe limbal stem cell deficiency due to burns in the eye.[8]

In March 2016 GlaxoSmithKline's Strimvelis (GSK2696273) therapy for the treatment ADA-SCID was recommended for EU approval.[9]

Stem cells are being studied for a number of reasons. The molecules and exosomes released from stem cells are also being studied in an effort to make medications.[10]

Research has been conducted on the effects of stem cells on animal models of brain degeneration, such as in Parkinson's, Amyotrophic lateral sclerosis, and Alzheimer's disease.[11][12][13] There have been preliminary studies related to multiple sclerosis.[14][15]

Healthy adult brains contain neural stem cells which divide to maintain general stem-cell numbers, or become progenitor cells. In healthy adult laboratory animals, progenitor cells migrate within the brain and function primarily to maintain neuron populations for olfaction (the sense of smell). Pharmacological activation of endogenous neural stem cells has been reported to induce neuroprotection and behavioral recovery in adult rat models of neurological disorder.[16][17][18]

Stroke and traumatic brain injury lead to cell death, characterized by a loss of neurons and oligodendrocytes within the brain. A small clinical trial was underway in Scotland in 2013, in which stem cells were injected into the brains of stroke patients.[19]

Clinical and animal studies have been conducted into the use of stem cells in cases of spinal cord injury.[20][21][22]

The pioneering work[23] by Bodo-Eckehard Strauer has now been discredited by the identification of hundreds of factual contradictions.[24] Among several clinical trials that have reported that adult stem-cell therapy is safe and effective, powerful effects have been reported from only a few laboratories, but this has covered old[25] and recent[26] infarcts as well as heart failure not arising from myocardial infarction.[27] While initial animal studies demonstrated remarkable therapeutic effects,[28][29] later clinical trials achieved only modest, though statistically significant, improvements.[30][31] Possible reasons for this discrepancy are patient age,[32] timing of treatment[33] and the recent occurrence of a myocardial infarction.[34] It appears that these obstacles may be overcome by additional treatments which increase the effectiveness of the treatment[35] or by optimizing the methodology although these too can be controversial. Current studies vary greatly in cell-procuring techniques, cell types, cell-administration timing and procedures, and studied parameters, making it very difficult to make comparisons. Comparative studies are therefore currently needed.

Stem-cell therapy for treatment of myocardial infarction usually makes use of autologous bone-marrow stem cells (a specific type or all), however other types of adult stem cells may be used, such as adipose-derived stem cells.[36] Adult stem cell therapy for treating heart disease was commercially available in at least five continents as of 2007.[citation needed]

Possible mechanisms of recovery include:[11]

It may be possible to have adult bone-marrow cells differentiate into heart muscle cells.[11]

The first successful integration of human embryonic stem cell derived cardiomyocytes in guinea pigs (mouse hearts beat too fast) was reported in August 2012. The contraction strength was measured four weeks after the guinea pigs underwent simulated heart attacks and cell treatment. The cells contracted synchronously with the existing cells, but it is unknown if the positive results were produced mainly from paracrine as opposed to direct electromechanical effects from the human cells. Future work will focus on how to get the cells to engraft more strongly around the scar tissue. Whether treatments from embryonic or adult bone marrow stem cells will prove more effective remains to be seen.[37]

In 2013 the pioneering reports of powerful beneficial effects of autologous bone marrow stem cells on ventricular function were found to contain "hundreds" of discrepancies.[38] Critics report that of 48 reports there seemed to be just five underlying trials, and that in many cases whether they were randomized or merely observational accepter-versus-rejecter, was contradictory between reports of the same trial. One pair of reports of identical baseline characteristics and final results, was presented in two publications as, respectively, a 578 patient randomized trial and as a 391 patient observational study. Other reports required (impossible) negative standard deviations in subsets of patients, or contained fractional patients, negative NYHA classes. Overall there were many more patients published as having receiving stem cells in trials, than the number of stem cells processed in the hospital's laboratory during that time. A university investigation, closed in 2012 without reporting, was reopened in July 2013.[39]

One of the most promising benefits of stem cell therapy is the potential for cardiac tissue regeneration to reverse the tissue loss underlying the development of heart failure after cardiac injury.[40]

Initially, the observed improvements were attributed to a transdifferentiation of BM-MSCs into cardiomyocyte-like cells.[28] Given the apparent inadequacy of unmodified stem cells for heart tissue regeneration, a more promising modern technique involves treating these cells to create cardiac progenitor cells before implantation to the injured area.[41]

The specificity of the human immune-cell repertoire is what allows the human body to defend itself from rapidly adapting antigens. However, the immune system is vulnerable to degradation upon the pathogenesis of disease, and because of the critical role that it plays in overall defense, its degradation is often fatal to the organism as a whole. Diseases of hematopoietic cells are diagnosed and classified via a subspecialty of pathology known as hematopathology. The specificity of the immune cells is what allows recognition of foreign antigens, causing further challenges in the treatment of immune disease. Identical matches between donor and recipient must be made for successful transplantation treatments, but matches are uncommon, even between first-degree relatives. Research using both hematopoietic adult stem cells and embryonic stem cells has provided insight into the possible mechanisms and methods of treatment for many of these ailments.[citation needed]

Fully mature human red blood cells may be generated ex vivo by hematopoietic stem cells (HSCs), which are precursors of red blood cells. In this process, HSCs are grown together with stromal cells, creating an environment that mimics the conditions of bone marrow, the natural site of red-blood-cell growth. Erythropoietin, a growth factor, is added, coaxing the stem cells to complete terminal differentiation into red blood cells.[42] Further research into this technique should have potential benefits to gene therapy, blood transfusion, and topical medicine.

In 2004, scientists at King's College London discovered a way to cultivate a complete tooth in mice[43] and were able to grow bioengineered teeth stand-alone in the laboratory. Researchers are confident that the tooth regeneration technology can be used to grow live teeth in human patients.

In theory, stem cells taken from the patient could be coaxed in the lab turning into a tooth bud which, when implanted in the gums, will give rise to a new tooth, and would be expected to be grown in a time over three weeks.[44] It will fuse with the jawbone and release chemicals that encourage nerves and blood vessels to connect with it. The process is similar to what happens when humans grow their original adult teeth. Many challenges remain, however, before stem cells could be a choice for the replacement of missing teeth in the future.[45][46]

Research is ongoing in different fields, alligators which are polyphyodonts grow up to 50 times a successional tooth (a small replacement tooth) under each mature functional tooth for replacement once a year.[47]

Heller has reported success in re-growing cochlea hair cells with the use of embryonic stem cells.[48]

Since 2003, researchers have successfully transplanted corneal stem cells into damaged eyes to restore vision. "Sheets of retinal cells used by the team are harvested from aborted fetuses, which some people find objectionable." When these sheets are transplanted over the damaged cornea, the stem cells stimulate renewed repair, eventually restore vision.[49] The latest such development was in June 2005, when researchers at the Queen Victoria Hospital of Sussex, England were able to restore the sight of forty patients using the same technique. The group, led by Sheraz Daya, was able to successfully use adult stem cells obtained from the patient, a relative, or even a cadaver. Further rounds of trials are ongoing.[50]

In April 2005, doctors in the UK transplanted corneal stem cells from an organ donor to the cornea of Deborah Catlyn, a woman who was blinded in one eye when acid was thrown in her eye at a nightclub. The cornea, which is the transparent window of the eye, is a particularly suitable site for transplants. In fact, the first successful human transplant was a cornea transplant. The absence of blood vessels within the cornea makes this area a relatively easy target for transplantation. The majority of corneal transplants carried out today are due to a degenerative disease called keratoconus.

The University Hospital of New Jersey reports that the success rate for growth of new cells from transplanted stem cells varies from 25 percent to 70 percent.[51]

In 2014, researchers demonstrated that stem cells collected as biopsies from donor human corneas can prevent scar formation without provoking a rejection response in mice with corneal damage.[52]

In January 2012, The Lancet published a paper by Steven Schwartz, at UCLA's Jules Stein Eye Institute, reporting two women who had gone legally blind from macular degeneration had dramatic improvements in their vision after retinal injections of human embryonic stem cells.[53]

In June 2015, the Stem Cell Ophthalmology Treatment Study (SCOTS), the largest adult stem cell study in ophthalmology ( http://www.clinicaltrials.gov NCT # 01920867) published initial results on a patient with optic nerve disease who improved from 20/2000 to 20/40 following treatment with bone marrow derived stem cells.[54]

Diabetes patients lose the function of insulin-producing beta cells within the pancreas.[55] In recent experiments, scientists have been able to coax embryonic stem cell to turn into beta cells in the lab. In theory if the beta cell is transplanted successfully, they will be able to replace malfunctioning ones in a diabetic patient.[56]

Human embryonic stem cells may be grown in cell culture and stimulated to form insulin-producing cells that can be transplanted into the patient.

However, clinical success is highly dependent on the development of the following procedures:[11]

Clinical case reports in the treatment orthopaedic conditions have been reported. To date, the focus in the literature for musculoskeletal care appears to be on mesenchymal stem cells. Centeno et al. have published MRI evidence of increased cartilage and meniscus volume in individual human subjects.[57][58] The results of trials that include a large number of subjects, are yet to be published. However, a published safety study conducted in a group of 227 patients over a 3-4-year period shows adequate safety and minimal complications associated with mesenchymal cell transplantation.[59]

Wakitani has also published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.[60]

Stem cells can also be used to stimulate the growth of human tissues. In an adult, wounded tissue is most often replaced by scar tissue, which is characterized in the skin by disorganized collagen structure, loss of hair follicles and irregular vascular structure. In the case of wounded fetal tissue, however, wounded tissue is replaced with normal tissue through the activity of stem cells.[61] A possible method for tissue regeneration in adults is to place adult stem cell "seeds" inside a tissue bed "soil" in a wound bed and allow the stem cells to stimulate differentiation in the tissue bed cells. This method elicits a regenerative response more similar to fetal wound-healing than adult scar tissue formation.[61] Researchers are still investigating different aspects of the "soil" tissue that are conducive to regeneration.[61]

Culture of human embryonic stem cells in mitotically inactivated porcine ovarian fibroblasts (POF) causes differentiation into germ cells (precursor cells of oocytes and spermatozoa), as evidenced by gene expression analysis.[62]

Human embryonic stem cells have been stimulated to form Spermatozoon-like cells, yet still slightly damaged or malformed.[63] It could potentially treat azoospermia.

In 2012, oogonial stem cells were isolated from adult mouse and human ovaries and demonstrated to be capable of forming mature oocytes.[64] These cells have the potential to treat infertility.

Destruction of the immune system by the HIV is driven by the loss of CD4+ T cells in the peripheral blood and lymphoid tissues. Viral entry into CD4+ cells is mediated by the interaction with a cellular chemokine receptor, the most common of which are CCR5 and CXCR4. Because subsequent viral replication requires cellular gene expression processes, activated CD4+ cells are the primary targets of productive HIV infection.[65] Recently scientists have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC).[66]

On 23 January 2009, the US Food and Drug Administration gave clearance to Geron Corporation for the initiation of the first clinical trial of an embryonic stem-cell-based therapy on humans. The trial aimed evaluate the drug GRNOPC1, embryonic stem cell-derived oligodendrocyte progenitor cells, on patients with acute spinal cord injury. The trial was discontinued in November 2011 so that the company could focus on therapies in the "current environment of capital scarcity and uncertain economic conditions".[67] In 2013 biotechnology and regenerative medicine company BioTime (NYSEMKT:BTX) acquired Geron's stem cell assets in a stock transaction, with the aim of restarting the clinical trial.[68]

Scientists have reported that MSCs when transfused immediately within few hours post thawing may show reduced function or show decreased efficacy in treating diseases as compared to those MSCs which are in log phase of cell growth(fresh), so cryopreserved MSCs should be brought back into log phase of cell growth in invitro culture before these are administered for clinical trials or experimental therapies, re-culturing of MSCs will help in recovering from the shock the cells get during freezing and thawing. Various clinical trials on MSCs have failed which used cryopreserved product immediately post thaw as compared to those clinical trials which used fresh MSCs.[69]

Research currently conducted on horses, dogs, and cats can benefit the development of stem cell treatments in veterinary medicine and can target a wide range of injuries and diseases such as myocardial infarction, stroke, tendon and ligament damage, osteoarthritis, osteochondrosis and muscular dystrophy both in large animals, as well as humans.[70][71][72][73] While investigation of cell-based therapeutics generally reflects human medical needs, the high degree of frequency and severity of certain injuries in racehorses has put veterinary medicine at the forefront of this novel regenerative approach.[74] Companion animals can serve as clinically relevant models that closely mimic human disease.[75][76]

There is widespread controversy over the use of human embryonic stem cells. This controversy primarily targets the techniques used to derive new embryonic stem cell lines, which often requires the destruction of the blastocyst. Opposition to the use of human embryonic stem cells in research is often based on philosophical, moral, or religious objections.[110] There is other stem cell research that does not involve the destruction of a human embryo, and such research involves adult stem cells, amniotic stem cells, and induced pluripotent stem cells.

Stem-cell research and treatment was practiced in the People's Republic of China. The Ministry of Health of the People's Republic of China has permitted the use of stem-cell therapy for conditions beyond those approved of in Western countries. The Western World has scrutinized China for its failed attempts to meet international documentation standards of these trials and procedures.[111]

Since 2008 many universities, centers and doctors tried a diversity of methods; in Lebanon proliferation for stem cell therapy, in-vivo and in-vitro techniques were used, Thus this country is considered the launching place of the Regentime[112] procedure. http://www.researchgate.net/publication/281712114_Treatment_of_Long_Standing_Multiple_Sclerosis_with_Regentime_Stem_Cell_Technique The regenerative medicine also took place in Jordan and Egypt.[citation needed]

Stem-cell treatment is currently being practiced at a clinical level in Mexico. An International Health Department Permit (COFEPRIS) is required. Authorized centers are found in Tijuana, Guadalajara and Cancun. Currently undergoing the approval process is Los Cabos. This permit allows the use of stem cell.[citation needed]

In 2005, South Korean scientists claimed to have generated stem cells that were tailored to match the recipient. Each of the 11 new stem cell lines was developed using somatic cell nuclear transfer (SCNT) technology. The resultant cells were thought to match the genetic material of the recipient, thus suggesting minimal to no cell rejection.[113]

As of 2013, Thailand still considers Hematopoietic stem cell transplants as experimental. Kampon Sriwatanakul began with a clinical trial in October 2013 with 20 patients. 10 are going to receive stem-cell therapy for Type-2 diabetes and the other 10 will receive stem-cell therapy for emphysema. Chotinantakul's research is on Hematopoietic cells and their role for the hematopoietic system function in homeostasis and immune response.[114]

Today, Ukraine is permitted to perform clinical trials of stem-cell treatments (Order of the MH of Ukraine 630 "About carrying out clinical trials of stem cells", 2008) for the treatment of these pathologies: pancreatic necrosis, cirrhosis, hepatitis, burn disease, diabetes, multiple sclerosis, critical lower limb ischemia. The first medical institution granted the right to conduct clinical trials became the "Institute of Cell Therapy"(Kiev).

Other countries where doctors did stem cells research, trials, manipulation, storage, therapy: Brazil, Cyprus, Germany, Italy, Israel, Japan, Pakistan, Philippines, Russia, Switzerland, Turkey, United Kingdom, India, and many others.

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Bone marrow is the flexible tissue in the interior of bones. In humans, red blood cells are produced by cores of bone marrow in the heads of long bones in a process known as hematopoiesis.[2] On average, bone marrow constitutes 4% of the total body mass of humans; in an adult having 65 kilograms of mass (143 lbs), bone marrow typically accounts for approximately 2.6 kilograms (5.7lb). The hematopoietic component of bone marrow produces approximately 500 billion blood cells per day, which use the bone marrow vasculature as a conduit to the body's systemic circulation.[3] Bone marrow is also a key component of the lymphatic system, producing the lymphocytes that support the body's immune system.[4]

Bone marrow transplants can be conducted to treat severe diseases of the bone marrow, including certain forms of cancer such as leukemia. Additionally, bone marrow stem cells have been successfully transformed into functional neural cells,[5] and can also potentially be used to treat illnesses such as inflammatory bowel disease.[6]

The two types of bone marrow are "red marrow" (Latin: medulla ossium rubra), which consists mainly of hematopoietic tissue, and "yellow marrow" (Latin: medulla ossium flava), which is mainly made up of fat cells. Red blood cells, platelets, and most white blood cells arise in red marrow. Both types of bone marrow contain numerous blood vessels and capillaries. At birth, all bone marrow is red. With age, more and more of it is converted to the yellow type; only around half of adult bone marrow is red. Red marrow is found mainly in the flat bones, such as the pelvis, sternum, cranium, ribs, vertebrae and scapulae, and in the cancellous ("spongy") material at the epiphyseal ends of long bones such as the femur and humerus. Yellow marrow is found in the medullary cavity, the hollow interior of the middle portion of short bones. In cases of severe blood loss, the body can convert yellow marrow back to red marrow to increase blood cell production.

The stroma of the bone marrow is all tissue not directly involved in the marrow's primary function of hematopoiesis.[2] Yellow bone marrow makes up the majority of bone marrow stroma, in addition to smaller concentrations of stromal cells located in the red bone marrow. Though not as active as parenchymal red marrow, stroma is indirectly involved in hematopoiesis, since it provides the hematopoietic microenvironment that facilitates hematopoiesis by the parenchymal cells. For instance, they generate colony stimulating factors, which have a significant effect on hematopoiesis. Cell types that constitute the bone marrow stroma include:

In addition, the bone marrow contains hematopoietic stem cells, which give rise to the three classes of blood cells that are found in the circulation: white blood cells (leukocytes), red blood cells (erythrocytes), and platelets (thrombocytes).[7]

The bone marrow stroma contains mesenchymal stem cells (MSCs),[7] also known as marrow stromal cells. These are multipotent stem cells that can differentiate into a variety of cell types. MSCs have been shown to differentiate, in vitro or in vivo, into osteoblasts, chondrocytes, myocytes, adipocytes and beta-pancreatic islets cells.

The blood vessels of the bone marrow constitute a barrier, inhibiting immature blood cells from leaving the marrow. Only mature blood cells contain the membrane proteins, such as aquaporin and glycophorin, that are required to attach to and pass the blood vessel endothelium.[9]Hematopoietic stem cells may also cross the bone marrow barrier, and may thus be harvested from blood.

The red bone marrow is a key element of the lymphatic system, being one of the primary lymphoid organs that generate lymphocytes from immature hematopoietic progenitor cells.[4] The bone marrow and thymus constitute the primary lymphoid tissues involved in the production and early selection of lymphocytes. Furthermore, bone marrow performs a valve-like function to prevent the backflow of lymphatic fluid in the lymphatic system.

Biological compartmentalization is evident within the bone marrow, in that certain cell types tend to aggregate in specific areas. For instance, erythrocytes, macrophages, and their precursors tend to gather around blood vessels, while granulocytes gather at the borders of the bone marrow.[7]

Animal bone marrow has been used in cuisine worldwide for millennia, such as the famed Milanese Ossobuco.[citation needed]

The normal bone marrow architecture can be damaged or displaced by aplastic anemia, malignancies such as multiple myeloma, or infections such as tuberculosis, leading to a decrease in the production of blood cells and blood platelets. The bone marrow can also be affected by various forms of leukemia, which attacks its hematologic progenitor cells.[10] Furthermore, exposure to radiation or chemotherapy will kill many of the rapidly dividing cells of the bone marrow, and will therefore result in a depressed immune system. Many of the symptoms of radiation poisoning are due to damage sustained by the bone marrow cells.

To diagnose diseases involving the bone marrow, a bone marrow aspiration is sometimes performed. This typically involves using a hollow needle to acquire a sample of red bone marrow from the crest of the ilium under general or local anesthesia.[11]

On CT and plain film, marrow change can be seen indirectly by assessing change to the adjacent ossified bone. Assessment with MRI is usually more sensitive and specific for pathology, particularly for hematologic malignancies like leukemia and lymphoma. These are difficult to distinguish from the red marrow hyperplasia of hematopoiesis, as can occur with tobacco smoking, chronically anemic disease states like sickle cell anemia or beta thalassemia, medications such as granulocyte colony-stimulating factors, or during recovery from chronic nutritional anemias or therapeutic bone marrow suppression.[12] On MRI, the marrow signal is not supposed to be brighter than the adjacent intervertebral disc on T1 weighted images, either in the coronal or sagittal plane, where they can be assessed immediately adjacent to one another.[13] Fatty marrow change, the inverse of red marrow hyperplasia, can occur with normal aging,[14] though it can also be seen with certain treatments such as radiation therapy. Diffuse marrow T1 hypointensity without contrast enhancement or cortical discontinuity suggests red marrow conversion or myelofibrosis. Falsely normal marrow on T1 can be seen with diffuse multiple myeloma or leukemic infiltration when the water to fat ratio is not sufficiently altered, as may be seen with lower grade tumors or earlier in the disease process.[15]

Bone marrow examination is the pathologic analysis of samples of bone marrow obtained via biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, anemia, and pancytopenia. The bone marrow produces the cellular elements of the blood, including platelets, red blood cells and white blood cells. While much information can be gleaned by testing the blood itself (drawn from a vein by phlebotomy), it is sometimes necessary to examine the source of the blood cells in the bone marrow to obtain more information on hematopoiesis; this is the role of bone marrow aspiration and biopsy.

The ratio between myeloid series and erythroid cells is relevant to bone marrow function, and also to diseases of the bone marrow and peripheral blood, such as leukemia and anemia. The normal myeloid-to-erythroid ratio is around 3:1; this ratio may increase in myelogenous leukemias, decrease in polycythemias, and reverse in cases of thalassemia.[16]

In a bone marrow transplant, hematopoietic stem cells are removed from a person and infused into another person (allogenic) or into the same person at a later time (autologous). If the donor and recipient are compatible, these infused cells will then travel to the bone marrow and initiate blood cell production. Transplantation from one person to another is conducted for the treatment of severe bone marrow diseases, such as congenital defects, autoimmune diseases or malignancies. The patient's own marrow is first killed off with drugs or radiation, and then the new stem cells are introduced. Before radiation therapy or chemotherapy in cases of cancer, some of the patient's hematopoietic stem cells are sometimes harvested and later infused back when the therapy is finished to restore the immune system.[17]

Bone marrow stem cells can be induced to become neural cells to treat neurological illnesses,[5] and can also potentially be used for the treatment of other illnesses, such as inflammatory bowel disease.[6] In 2013, following a clinical trial, scientists proposed that bone marrow transplantation could be used to treat HIV in conjunction with antiretroviral drugs;[18][19] however, it was later found that HIV remained in the bodies of the test subjects.[20]

The stem cells are typically harvested directly from the red marrow in the iliac crest, often under general anesthesia. The procedure is minimally invasive and does not require stitches afterwards. Depending on the donor's health and reaction to the procedure, the actual harvesting can be an outpatient procedure, or can require 12 days of recovery in the hospital.[21]

Another option is to administer certain drugs that stimulate the release of stem cells from the bone marrow into circulating blood.[22] An intravenous catheter is inserted into the donor's arm, and the stem cells are then filtered out of the blood. This procedure is similar to that used in blood or platelet donation. In adults, bone marrow may also be taken from the sternum, while the tibia is often used when taking samples from infants.[11] In newborns, stem cells may be retrieved from the umbilical cord.[23]

The earliest fossilised evidence of bone marrow was discovered in 2014 in Eusthenopteron, a lobe-finned fish which lived during the Devonian period approximately 370 million years ago.[24] Scientists from Uppsala University and the European Synchrotron Radiation Facility used X-ray synchrotron microtomography to study the fossilised interior of the skeleton's humerus, finding organised tubular structures akin to modern vertebrate bone marrow.[24]Eusthenopteron is closely related to the early tetrapods, which ultimately evolved into the land-dwelling mammals and lizards of the present day.[24]

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J R Soc Med. 2004 Oct; 97(10): 465471.

Institute of Medical Sciences, University of Lincoln, UK

An area of research that today generates great optimism is the use of stem cells for therapy of human diseases. Much of the excitement centres on embryonic stem cells, but this approach remains controversial for ethical reasons; moreover, routine clinical application of this strategy is many years away. By contrast, haematopoietic stem cells from adult bone marrow are well characterized and have long been used therapeutically.1 An adult weighing 70 kg has a functional haematopoietic marrow volume of about 1.75 L and upon increased demands such as infection or haemorrhage it can increase sixfold.1,2 No moral controversy surrounds the use of these cells since they are either autologous or collected from a consenting donor. The potential applications of adult bone marrow cells have gained momentum with discoveries relating to the mesenchymal stem cell.

Adult bone-marrow-derived mesenchymal stem cells (MSC) are capable of differentiation along several lineages ().315 They are positive for CD29, CD44, CD105 and CD166, have a doubling time of about two days, expand in culture up to sixfold and their biological functions are not altered by ageing.3,15 lists some of the cytokine receptors expressed by these cells and the cytokines produced. Their features and properties are closely similar to those of counterpart cells isolated from fetal blood, liver and bone in the first and second trimesters, from amniotic fluid and umbilical cord blood, and from adult peripheral blood, compact bone and adipose tissue.2127 Moreover, a CD133-positive subpopulation of these cells, which can be expanded under defined conditions for more than one hundred population doublings without telomere shortening or karyotypic abnormality, has proved capable of differentiation not only into mesenchymal cell types (osteoblasts, chondrocytes, adipocytes, myocytes) but also into endothelium and cells with neuroectodermal phenotype and function.2830 Previously, adult marrow-derived stem cells were believed to yield a limited number of cell types whereas embryonic cells were totipotent. The discovery of these multipotent adult stem cells has clearly narrowed the gap: they offer a very promising and much more abundant potential resource for therapy of inherited or degenerative diseases and for repair of tissues such as cartilage, bone and myocardium.

What is the mechanism of stem cell differentiation? When the phenomenon was first explored, the possibility of cell fusion was mootedthat is, hybridization with other cells rather than true plasticity. Indeed, embryonic stem cells were seen to hybridize with brain cells to form tetraploid cells with pluripotent character.31 However, in-vitro and in-vivo studies of adult bone marrow stem cells suggest a rate of cell fusion too low to account for the transdifferentiation.32 Moreover, single euploid bone marrow MSC, never co-cultured with tissue-specific cells or embryonic cells, have been seen to differentiate into cells of the three germ layers;33in vivo, the use of bone marrow cells selectively expressing the enhanced green fluorescent protein ruled out fusion as a mechanism for the generation of functional pancreatic islet beta cells;34 and hepatocytes, cardiomyocytes, and pancreatic and endothelial cells have been described as physiologically either diploid or polyploid.3537 Certain cytokines, including interleukins (IL) 1, 4, and 13, tumour necrosis factor alpha and interferon gamma, are involved in the generation of normal multinucleated cells such as osteoclasts and Langhans giant cells;3840 thus, observations suggesting fusion of bone marrow cells with, for example, Purkinje neurons, cardiomyocytes and hepatocytes41 may instead simply reflect physiological polyploidy.

The direction in which bone marrow MSC differentiate is heavily influenced by cytokines (). For example, bone morphogenetic protein 6 (BMP-6) not only influences differentiation towards chondrogenesis or osteogenesis but may also serve to regulate the bone marrow environment via the effects of IL-6 on haematopoiesis and osteogenesis.50 Two possible mechanisms have been proposed for a regulatory role of BMP-6 in the human bone marrow microenvironment: (i) it might enhance the osteoblastic differentiation of human MSC; or (ii) it might reduce the osteoclastic differentiation of haematopoietic marrow cells by decreasing interleukin-6 production in bone marrow stroma. MSC coexpressing CD133 and fetal liver kinase 1 generated endothelial cells in the presence of vascular endothelial growth factor, and functional hepatocytes in the presence of fibroblast growth factor-4 and hepatocyte growth factor.29,30 Also, MSC coexpressing CD133, CD172 and nestin differentiated along a neural pathway in the presence of fibroblast growth factor or retinoic acid plus nerve growth factor.51,54 An MSC side-population with high efflux of DNA binding dye and expressing CD90 (Thy1) differentiated into mesangial renal cells.55

In-vitro differentiation conditions of human adult bone marrow mesenchymal stem cell

In animal models, transplanted bone marrow cells have been detected in skeletal and cardiac muscle,5658 vascular endothelium,58,59 liver,6062 lung, gut and skin epithelia,62 pancreatic beta cell islets,34,63 renal glomeruli,14,55 and neural tissue.33,6469 When bone-marrow-derived MSC were injected intracerebrally in acid-sphingomyelinase-deficient mice, the onset of neurological abnormalities was delayed and the animals lifespan was extended.70 Local transplantation of such cells is also reported to have regenerated bone7173 and myocardium.74,75 It is noteworthy that no donor-derived tumours have been seen in these animal modelswhereas with transplantation of undifferentiated embryonic stem cells teratoma development has been reported.76 The results also differ from those of undifferentiated embryonic stem cell transplantation in that engraftment and tissue-specific differentiation are achieved without pretransplantation measures to induce differentiation down the lineage desired. The ability of marrow-derived cells to populate numerous body tissuesbone, liver, cardiac muscle, colon, skinis well shown in patients who have received cells from gender-mismatched donors ().7784 A postmortem study revealed donor-derived neurons in the hippocampus and cerebral cortex of brain samples from women who had received bone marrow transplants from men.85 Deductions from such findings must be qualified by the observation that women who have carried male fetuses may show long-term mosaicism with male cells; nevertheless, the weight of the evidence is that donor bone-marrow-derived cells can migrate and give rise to tissues belonging to all three germ-cell layers.7785 It is noteworthy that, in the transdifferentiation of these adult marrow stem cells, there was no evidence of cell fusion.7785 Lately, work in mice indicated that such cells participate in skin regeneration and reconstitution and promote wound healing;8688 and one research group reports a pilot study in three patients indicating that locally applied autologous bone marrow cells enhanced dermal building and closure of long-term non-healing wounds.89

Migration of human adult bone marrow stem cells in gender-mismatched bone marrow transplantation patients

In animal models of myocardial infarction, stem cells were reported to participate in repair whether injected locally or stimulated in bone marrow by use of stem cell factor (SCF) and G-CSF.90 In man, a randomized placebo-controlled study revealed increased coronary collateral flow in patients treated with intracoronary GM-CSF (molgramostim) followed by two weeks of subcutaneous administration.91

In the past decade the use of G-CSF (filgrastim) has transformed the treatment of cancer by facilitating marrow reconstitution after myeloablative therapy. We must hope for a similar breakthrough in the management of coronary heart disease.

In allogeneic transplantation, mesenchymal stem cells in bone marrow play a key part in immunomodulation and the induction of tolerance. MSC suppress the proliferation of T-lymphocytes induced by cellular or non-specific mitogenic stimuli92 and negatively influence B-cell lymphopoiesis.93 Allogeneic/xenogeneic MSC transplants engraft in immunocompetent sheep and non-human primates.9497 When a patient was treated, after myeloablation, with both haematopoietic stem cells and cultured MSC from a mismatched donor, only grade I graft-versus-host disease (GvHD) was observed.98 That MSC can not only reduce GvHD but also facilitate haematopoietic engraftment is evidenced by the rapid haematopoietic recovery of patients with breast cancer who received autologous blood stem cells together with culture-expanded MSC after high-dose chemotherapy.99 In both clinical trials, MSC transplantation was well tolerated.

Osteogenesis imperfecta has been the focus of two studies in children. Allogeneic MSC transplantation, leading to successful osteoblast engraftment in 3 of 5 children with type III osteogenesis imperfecta, was associated with a 4477% increase in bone mineral content, improved linear growth and reduced fracture frequency.77,100 In another cohort of 6 children with type III osteogenesis imperfecta who had received earlier bone marrow transplantation, MSC infusions from the original donor resulted in a 50% improvement in their growth velocity.101 Similar improvements were observed in children with metachromatic leukodystrophy and Hurlers syndrome after repeated allogeneic marrow MSC infusions.102

Ten clinical studies have been reported on the effects of autologous bone marrow stem cell transplantation in patients with myocardial infarction or ischaemic heart failure ().103112 In three pilot studies, two of them randomized controlled trials, bone marrow cells infused via a coronary catheter a few days after acute myocardial infarction led to significant improvement in coronary flow reserve and left ventricular ejection fraction.104,105,111 In the remaining seven, marrow cells injected directly into the myocardium of patients with chronic ischaemic heart disease yielded benefits in ejection fraction and also angina score.103,106110,112

Clinical trials of adult bone marrow autotransplantation in ischaemic heart disease

Despite the impressive safety record of all these pilot clinical trials, the possibility of undesired differentiation into other tissues must be borne in mind in monitoring of future studies.

In the next decade, the approaches discussed above will clearly be developed and refined. Further avenues will open up. For example, bone-marrow-derived cells expressing stem cell factor have been shown to initiate endogenous pancreatic tissue regeneration in mice.113 If such cells could be used as pancreatic beta islet cell progenitors, there would be scope for autologous transplantation in patients with diabetes, avoiding the need for the immunosuppression necessary after allotransplantation and circumventing the scarcity of allogeneic material. Whereas the multipotent adult dermal stem cells from human scalp skin have shown mainly neural differentiation, suggesting a possible therapeutic role in neurodegenerative diseases,114,115 the bone marrow MSC show strong orientation towards bone, cartilage, endothelium and cardiac muscle.

In conclusion, the existing medical uses of bone marrow are likely to expand greatly with exploitation of the therapeutic potential of adult mesenchymal stem cells, with their capacity for many lines of differentiation. The next stage is to isolate the various subsets and investigate their mechanisms of differentiation and homing to tissues. This work has vast implications for human wellbeing, through cell and gene therapies, through tissue engineering and through immunotherapy.

1. Hassan HT, Gutensohn K, Zander AR, Kuhnl P. CD34 positive cell sorting and enrichment: applications in bloodbanking and transplantation. In: Recktenwald D, Radbruch A, eds. Cell Separation: Methods and Applications. New York: Marcel Dekker, 1998: 28392

9. Sanchez-Ramos J, Song S, Cardozo-Pelaez F, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 2002;174: 1120

73. Kadiyala S, Jaiswal N, Bruder SP. Culture-expanded bone marrow-derived mesenchymal stem cells regenerate a critical-sized bone defect. Tissue Eng 9197;3: 17385

Articles from Journal of the Royal Society of Medicine are provided here courtesy of Royal Society of Medicine Press

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Adult bone-marrow stem cells and their potential in medicine

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In 2006, Shinya Yamanaka of Kyoto University in Japan was the first to disprove the previous notion that reversible cell differentiation of mammals was impossible. He reprogrammed a fully differentiated mouse cell into a pluripotent stem cell by introducing four genes, Oct-4, SOX2, KLF4, and Myc, into the mouse fibroblast through gene-carrying viruses. With this method, he and his coworkers created induced pluripotent stem cells (iPS cells), the key component in this experiment.[1] Scientists have been able to conduct experiments that show the ability of iPS cells to treat and even cure diseases. In this experiment, tests were run on mice with inherited sickle-cell anemia. Skin cells were turned into cells containing genes that transformed the cells into iPS cells. These replaced the diseased sickled cells, curing the test mice. The reprogramming of the pluripotent stem cells in mice was successfully duplicated with human pluripotent stem cells within about a year of the experiment on the mice.[citation needed]

Sickle-cell anemia is a disease in which the body produces abnormally shaped red blood cells. Red blood cells are flexible and round, moving easily through the blood vessels. Infected cells are shaped like a crescent or sickle (the namesake of the disease). As a result of this disorder the hemoglobin protein in red blood cells is faulty. Normal hemoglobin bonds to oxygen, then releases it into cells that need it. The blood cell retains its original form and is cycled back to the lungs and re-oxygenated.

Sickle cell hemoglobin, however, after giving up oxygen, cling together and make the red blood cell stiff. The sickle shape also makes it difficult for the red blood cell to navigate arteries and causes blockages.[2] This can cause intense pain and organ damage. The sickled red blood cells are fragile and prone to rupture. When the number of red blood cells decreases from rupture (hemolysis), anemia is the result. Sickle cells die in 1020 days as opposed to the traditional 120-day lifespan of a normal red blood cell.

Sickle cell anemia is inherited as an autosomal (meaning that the gene is not linked to a sex chromosome) recessive condition.[2] This means that the gene can be passed on from a carrier to his or her children. In order for sickle cell anemia to affect a person, the gene must be inherited from both the mother and the father, so that the child has two recessive sickle cell genes (a homozygous inheritance). People who inherit one sickle cell gene from one parent and one normal gene from the other parent, i.e. heterozygous patients, have a condition called sickle cell trait. Their bodies make both sickle hemoglobin and normal hemoglobin. They may pass the trait on to their children.

The effects of sickle-cell anemia vary from person to person. People who have the disease suffer from varying degrees of chronic pain and fatigue. With proper care and treatment, the quality of health of most patients will improve. Doctors have learned a great deal about sickle cell anemia since its discovery in 1979. They know its causes, its effects on the body, and possible treatments for complications. Sickle cell anemia has no widely available cure. A bone marrow transplant is the only treatment method currently recognized to be able to cure the disease, though it does not work for every patient. Finding a donor is difficult and the procedure could potentially do more harm than good. Treatments for sickle cell anemia are generally aimed at avoiding crises, relieving symptoms, and preventing complications. Such treatments may include medications, blood transfusions, and supplemental oxygen.

During the first step of the experiment, skin cells (also known as fibroblasts) were collected from infected test mice and put in a culture. The fibroblasts were reprogrammed by infecting them with retroviruses that contained genes common to embryonic stem cells. These genes were the same four used by Yamanaka (Oct-4, SOX2, KLF4, and Myc) in his earlier study. The investigators were trying to produce cells with the potential to differentiate into any type of cell needed (i.e. pluripotent stem cells). As the experiment continued, the fibroblasts multiplied into identical copies of iPS cells. The cells were then treated to form the mutation needed to reverse the anemia in the mice. This was accomplished by restructuring the DNA containing the defective globin gene into DNA with the normal gene through the process of homologous recombination. The iPS cells then differentiated into blood stem cells, or hematopoietic stem cells. The hematopoietic cells were injected back into the infected mice, where they proliferate and differentiate into normal blood cells, curing the mice of the disease.[3][4][verification needed]

To determine whether the mice were cured from the disease, the scientists checked for the usual symptoms of sickle cell disease. They examined the blood for mean corpuscular volume (MCV) and red cell distribution width (RDW) and urine concentration defects. They also checked for sickled red blood cells. They examined the DNA through gel electrophoresis, checking for bands that display an allele that causes sickling. Compared to the untreated mice with the disease, which they used as a control, "the treated animals had marked increases in RBC counts, healthy hemoglobin, and packed cell volume levels".[5]

Researchers examined "the urine concentration defect, which results from RBC sickling in renal tubules and consequent reduction in renal medullary blood flow, and the general deteriorated systemic condition reflected by lower body weight and increased breathing."[5] They were able to see that these parts of the body of the mice had healed or improved. This indicated that "all hematological and systemic parameters of sickle cell anemia improved substantially and were comparable to those in control mice."[5] They cannot say if this will work in humans because a safe way to inject the genes for the induced pluripotent cells is still needed.[citation needed]

The reprogramming of the induced pluripotent stem cells in mice was successfully duplicated in humans within a year of the successful experiment on the mice. This reprogramming was done in several labs and it was shown that the iPS cells in humans were almost identical to original embryonic stem cells (ES cells) that are responsible for the creation of all structures in a fetus.[1] An important feature of iPS cells is that they can be generated with cells taken from an adult, which would circumvent many of the ethical problems associated with working with ES cells. These iPS cells also have potential in creating and examining new disease models and developing more efficient drug treatments.[6] Another feature of these cells is that they provide researchers with a human cell sample, as opposed to simply using an animal with similar DNA, for drug testing.

One major problem with iPS cells is the way in which the cells are reprogrammed. Using gene-carrying viruses has the potential to cause iPS cells to develop into cancerous cells.[1] Also, an implant made using undifferentiated iPS cells, could cause a teratoma to form. Any implant that is generated from using these iPS cells would only be viable for transplant into the original subject that the cells were taken from. In order for these iPS cells to become viable in therapeutic use, there are still many steps that must be taken.[5][7]

In the future, researchers hope that induced pluripotent cells may be used to treat other diseases. Pluripotency is a crucial part of disease treatment because iPS cells are capable of differentiation in a way that is very similar to embryonic stem cells which can grow into fully differentiated tissues. iPS cells also demonstrate high telomerase activity and express human telomerase reverse transcriptase, a necessary component in the telomerase protein complex. Also, iPS cells expressed cell surface antigenic markers expressed on ES cells. Also, doubling time and mitotic activity are cornerstones of ES cells, as stem cells must self-renew as part of their definition. As said, iPS cells are morphologically similar to embryonic stem cells. Each cell has a round shape, a large nucleolus and a small amount of cytoplasm. One day, the process may be used in practical settings to provide a fundamental way of regeneration.

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Induced pluripotent stem-cell therapy - Wikipedia

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The membrane scaffold SLP2 anchors a proteolytic hub in mitochondria containing PARL and the iAAA protease YME1L

These authors contributed equally to this work

The membrane scaffold SLP2 anchors a large protease complex containing the rhomboid protease PARL and the iAAA protease YME1L in the inner membrane of mitochondria, termed the SPY complex. Assembly into the SPY complex modulates PARL activity toward its substrate proteins PINK1 and PGAM5.

The membrane scaffold SLP2 anchors a large protease complex containing the rhomboid protease PARL and the iAAA protease YME1L in the inner membrane of mitochondria, termed the SPY complex. Assembly into the SPY complex modulates PARL activity toward its substrate proteins PINK1 and PGAM5.

SLP2 assembles with PARL and YME1L into the SPY complex in the mitochondrial inner membrane.

Assembly into SPY complexes modulates PARLmediated processing of PINK1 and PGAM5.

SLP2 restricts OMA1mediated processing of the OPA1.

Timothy Wai, Shotaro Saita, Hendrik Nolte, Sebastian Mller, Tim Knig, Ricarda RichterDennerlein, HansGeorg Sprenger, Joaquin Madrenas, Mareike Mhlmeister, Ulrich Brandt, Marcus Krger, Thomas Langer

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Supercourse: Epidemiology, the Internet, and Global Health

Cardiac Stem Cells Comments Off on Supercourse: Epidemiology, the Internet, and Global Health | October 16th, 2016

Persons using assistive technology might not be able to fully access information in this file. For assistance, please send e-mail to: mmwrq@cdc.gov. Type 508 Accommodation and the title of the report in the subject line of e-mail.

Please note: An erratum has been published for this article. To view the erratum, please click here.

Clare A. Dykewicz, M.D., M.P.H. Harold W. Jaffe, M.D., Director Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases Division of HIV/AIDS Prevention --- Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention

Clare A. Dykewicz, M.D., M.P.H., Chair Harold W. Jaffe, M.D. Thomas J. Spira, M.D. Division of AIDS, STD, and TB Laboratory Research

William R. Jarvis, M.D. Hospital Infections Program National Center for Infectious Diseases, CDC

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases Division of HIV/AIDS Prevention --- Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention, CDC

Brian R. Edlin, M.D. Division of HIV/AIDS Prevention---Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention, CDC

Robert T. Chen, M.D., M.A. Beth Hibbs, R.N., M.P.H. Epidemiology and Surveillance Division National Immunization Program, CDC

Raleigh A. Bowden, M.D. Keith Sullivan, M.D. Fred Hutchinson Cancer Research Center Seattle, Washington

David Emanuel, M.B.Ch.B. Indiana University Indianapolis, Indiana

David L. Longworth, M.D. Cleveland Clinic Foundation Cleveland, Ohio

Philip A. Rowlings, M.B.B.S., M.S. International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry Milwaukee, Wisconsin

Robert H. Rubin, M.D. Massachusetts General Hospital Boston, Massachusetts and Massachusetts Institute of Technology Cambridge, Massachusetts

Kent A. Sepkowitz, M.D. Memorial-Sloan Kettering Cancer Center New York, New York

John R. Wingard, M.D. University of Florida Gainesville, Florida

John F. Modlin, M.D. Dartmouth Medical School Hanover, New Hampshire

Donna M. Ambrosino, M.D. Dana-Farber Cancer Institute Boston, Massachusetts

Norman W. Baylor, Ph.D. Food and Drug Administration Rockville, Maryland

Albert D. Donnenberg, Ph.D. University of Pittsburgh Pittsburgh, Pennsylvania

Pierce Gardner, M.D. State University of New York at Stony Brook Stony Brook, New York

Roger H. Giller, M.D. University of Colorado Denver, Colorado

Neal A. Halsey, M.D. Johns Hopkins University Baltimore, Maryland

Chinh T. Le, M.D. Kaiser-Permanente Medical Center Santa Rosa, California

Deborah C. Molrine, M.D. Dana-Farber Cancer Institute Boston, Massachusetts

Keith M. Sullivan, M.D. Fred Hutchinson Cancer Research Center Seattle, Washington

CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation have cosponsored these guidelines for preventing opportunistic infections (OIs) among hematopoietic stem cell transplant (HSCT) recipients. The guidelines were drafted with the assistance of a working group of experts in infectious diseases, transplantation, and public health. For the purposes of this report, HSCT is defined as any transplantation of blood- or marrow-derived hematopoietic stem cells, regardless of transplant type (i.e., allogeneic or autologous) or cell source (i.e., bone marrow, peripheral blood, or placental or umbilical cord blood). Such OIs as bacterial, viral, fungal, protozoal, and helminth infections occur with increased frequency or severity among HSCT recipients. These evidence-based guidelines contain information regarding preventing OIs, hospital infection control, strategies for safe living after transplantation, vaccinations, and hematopoietic stem cell safety. The disease-specific sections address preventing exposure and disease for pediatric and adult and autologous and allogeneic HSCT recipients. The goal of these guidelines is twofold: to summarize current data and provide evidence-based recommendations regarding preventing OIs among HSCT patients. The guidelines were developed for use by HSCT recipients, their household and close contacts, transplant and infectious diseases physicians, HSCT center personnel, and public health professionals. For all recommendations, prevention strategies are rated by the strength of the recommendation and the quality of the evidence supporting the recommendation. Adhering to these guidelines should reduce the number and severity of OIs among HSCT recipients.

In 1992, the Institute of Medicine (1) recommended that CDC lead a global effort to detect and control emerging infectious agents. In response, CDC published a plan (2) that outlined national disease prevention priorities, including the development of guidelines for preventing opportunistic infections (OIs) among immunosuppressed persons. During 1995, CDC published guidelines for preventing OIs among persons infected with human immunodeficiency virus (HIV) and revised those guidelines during 1997 and 1999 (3--5). Because of the success of those guidelines, CDC sought to determine the need for expanding OI prevention activities to other immunosuppressed populations. An informal survey of hematology, oncology, and infectious disease specialists at transplant centers and a working group formed by CDC determined that guidelines were needed to help prevent OIs among hematopoietic stem cell transplant (HSCT)* recipients.

The working group defined OIs as infections that occur with increased frequency or severity among HSCT recipients, and they drafted evidence-based recommendations for preventing exposure to and disease caused by bacterial, fungal, viral, protozoal, or helminthic pathogens. During March 1997, the working group presented the first draft of these guidelines at a meeting of representatives from public and private health organizations. After review by that group and other experts, these guidelines were revised and made available during September 1999 for a 45-day public comment period after notification in the Federal Register. Public comments were added when feasible, and the report was approved by CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. The pediatric content of these guidelines has been endorsed also by the American Academy of Pediatrics. The hematopoietic stem cell safety section was endorsed by the International Society of Hematotherapy and Graft Engineering.

The first recommendations presented in this report are followed by recommendations for hospital infection control, strategies for safe living, vaccinations, and hematopoietic stem cell safety. Unless otherwise noted, these recommendations address allogeneic and autologous and pediatric and adult HSCT recipients. Additionally, these recommendations are intended for use by the recipients, their household and other close contacts, transplant and infectious diseases specialists, HSCT center personnel, and public health professionals.

For all recommendations, prevention strategies are rated by the strength of the recommendation (Table 1) and the quality of the evidence (Table 2) supporting the recommendation. The principles of this rating system were developed by the Infectious Disease Society of America and the U.S. Public Health Service for use in the guidelines for preventing OIs among HIV-infected persons (3--6). This rating system allows assessments of recommendations to which adherence is critical.

HSCT is the infusion of hematopoietic stem cells from a donor into a patient who has received chemotherapy, which is usually marrow-ablative. Increasingly, HSCT has been used to treat neoplastic diseases, hematologic disorders, immunodeficiency syndromes, congenital enzyme deficiencies, and autoimmune disorders (e.g., systemic lupus erythematosus or multiple sclerosis) (7--10). Moreover, HSCT has become standard treatment for selected conditions (7,11,12). Data from the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry indicate that approximately 20,000 HSCTs were performed in North America during 1998 (Statistical Center of the International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry, unpublished data, 1998).

HSCTs are classified as either allogeneic or autologous on the basis of the source of the transplanted hematopoietic progenitor cells. Cells used in allogeneic HSCTs are harvested from a donor other than the transplant recipient. Such transplants are the most effective treatment for persons with severe aplastic anemia (13) and offer the only curative therapy for persons with chronic myelogenous leukemia (12). Allogeneic donors might be a blood relative or an unrelated donor. Allogeneic transplants are usually most successful when the donor is a human lymphocyte antigen (HLA)-identical twin or matched sibling. However, for allogeneic candidates who lack such a donor, registry organizations (e.g., the National Marrow Donor Program) maintain computerized databases that store information regarding HLA type from millions of volunteer donors (14--16). Another source of stem cells for allogeneic candidates without an HLA-matched sibling is a mismatched family member (17,18). However, persons who receive allogeneic grafts from donors who are not HLA-matched siblings are at a substantially greater risk for graft-versus-host disease (GVHD) (19). These persons are also at increased risk for suboptimal graft function and delayed immune system recovery (19). To reduce GVHD among allogeneic HSCTs, techniques have been developed to remove T-lymphocytes, the principal effectors of GVHD, from the donor graft. Although the recipients of T-lymphocyte--depleted marrow grafts generally have lower rates of GVHD, they also have greater rates of graft rejection, cytomegalovirus (CMV) infection, invasive fungal infection, and Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (20).

The patient's own cells are used in an autologous HSCT. Similar to autologous transplants are syngeneic transplants, among whom the HLA-identical twin serves as the donor. Autologous HSCTs are preferred for patients who require high-level or marrow-ablative chemotherapy to eradicate an underlying malignancy but have healthy, undiseased bone marrows. Autologous HSCTs are also preferred when the immunologic antitumor effect of an allograft is not beneficial. Autologous HSCTs are used most frequently to treat breast cancer, non-Hodgkin's lymphoma, and Hodgkin's disease (21). Neither autologous nor syngeneic HSCTs confer a risk for chronic GVHD.

Recently, medical centers have begun to harvest hematopoietic stem cells from placental or umbilical cord blood (UCB) immediately after birth. These harvested cells are used primarily for allogeneic transplants among children. Early results demonstrate that greater degrees of histoincompatibility between donor and recipient might be tolerated without graft rejection or GVHD when UCB hematopoietic cells are used (22--24). However, immune system function after UCB transplants has not been well-studied.

HSCT is also evolving rapidly in other areas. For example, hematopoietic stem cells harvested from the patient's peripheral blood after treatment with hematopoietic colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF or filgastrim] or granulocyte-macrophage colony-stimulating factor [GM-CSF or sargramostim]) are being used increasingly among autologous recipients (25) and are under investigation for use among allogeneic HSCT. Peripheral blood has largely replaced bone marrow as a source of stem cells for autologous recipients. A benefit of harvesting such cells from the donor's peripheral blood instead of bone marrow is that it eliminates the need for general anesthesia associated with bone marrow aspiration.

GVHD is a condition in which the donated cells recognize the recipient's cells as nonself and attack them. Although the use of intravenous immunoglobulin (IVIG) in the routine management of allogeneic patients was common in the past as a means of producing immune modulation among patients with GVHD, this practice has declined because of cost factors (26) and because of the development of other strategies for GVHD prophylaxis (27). For example, use of cyclosporine GVHD prophylaxis has become commonplace since its introduction during the early 1980s. Most frequently, cyclosporine or tacrolimus (FK506) is administered in combination with other immunosuppressive agents (e.g., methotrexate or corticosteroids) (27). Although cyclosporine is effective in preventing GVHD, its use entails greater hazards for infectious complications and relapse of the underlying neoplastic disease for which the transplant was performed.

Although survival rates for certain autologous recipients have improved (28,29), infection remains a leading cause of death among allogeneic transplants and is a major cause of morbidity among autologous HSCTs (29). Researchers from the National Marrow Donor Program reported that, of 462 persons receiving unrelated allogeneic HSCTs during December 1987--November 1990, a total of 66% had died by 1991 (15). Among primary and secondary causes of death, the most common cause was infection, which occurred among 37% of 307 patients (15).**

Despite high morbidity and mortality after HSCT, recipients who survive long-term are likely to enjoy good health. A survey of 798 persons who had received an HSCT before 1985 and who had survived for >5 years after HSCT, determined that 93% were in good health and that 89% had returned to work or school full time (30). In another survey of 125 adults who had survived a mean of 10 years after HSCT, 88% responded that the benefits of transplantation outweighed the side effects (31).

During the first year after an HSCT, recipients typically follow a predictable pattern of immune system deficiency and recovery, which begins with the chemotherapy or radiation therapy (i.e., the conditioning regimen) administered just before the HSCT to treat the underlying disease. Unfortunately, this conditioning regimen also destroys normal hematopoiesis for neutrophils, monocytes, and macrophages and damages mucosal progenitor cells, causing a temporary loss of mucosal barrier integrity. The gastrointestinal tract, which normally contains bacteria, commensal fungi, and other bacteria-carrying sources (e.g., skin or mucosa) becomes a reservoir of potential pathogens. Virtually all HSCT recipients rapidly lose all T- and B-lymphocytes after conditioning, losing immune memory accumulated through a lifetime of exposure to infectious agents, environmental antigens, and vaccines. Because transfer of donor immunity to HSCT recipients is variable and influenced by the timing of antigen exposure among donor and recipient, passively acquired donor immunity cannot be relied upon to provide long-term immunity against infectious diseases among HSCT recipients.

During the first month after HSCT, the major host-defense deficits include impaired phagocytosis and damaged mucocutaneous barriers. Additionally, indwelling intravenous catheters are frequently placed and left in situ for weeks to administer parenteral medications, blood products, and nutritional supplements. These catheters serve as another portal of entry for opportunistic pathogens from organisms colonizing the skin (e.g., . coagulase-negative Staphylococci, Staphylococcus aureus, Candida species, and Enterococci) (32,33).

Engraftment for adults and children is defined as the point at which a patient can maintain a sustained absolute neutrophil count (ANC) of >500/mm3 and sustained platelet count of >20,000, lasting >3 consecutive days without transfusions. Among unrelated allogeneic recipients, engraftment occurs at a median of 22 days after HSCT (range: 6--84 days) (15). In the absence of corticosteroid use, engraftment is associated with the restoration of effective phagocytic function, which results in a decreased risk for bacterial and fungal infections. However, all HSCT recipients and particularly allogeneic recipients, experience an immune system dysfunction for months after engraftment. For example, although allogeneic recipients might have normal total lymphocyte counts within >2 months after HSCT, they have abnormal CD4/CD8 T-cell ratios, reflecting their decreased CD4 and increased CD8 T-cell counts (27). They might also have immunoglobulin G (IgG)2, IgG4, and immunoglobulin A (IgA) deficiencies for months after HSCT and have difficulty switching from immunoglobulin M (IgM) to IgG production after antigen exposure (32). Immune system recovery might be delayed further by CMV infection (34).

During the first >2 months after HSCT, recipients might experience acute GVHD that manifests as skin, gastrointestinal, and liver injury, and is graded on a scale of I--IV (32,35,36). Although autologous or syngeneic recipients might occasionally experience a mild, self-limited illness that is acute GVHD-like (19,37), GVHD occurs primarily among allogeneic recipients, particularly those receiving matched, unrelated donor transplants. GVHD is a substantial risk factor for infection among HSCT recipients because it is associated with a delayed immunologic recovery and prolonged immunodeficiency (19). Additionally, the immunosuppressive agents used for GVHD prophylaxis and treatment might make the HSCT recipient more vulnerable to opportunistic viral and fungal pathogens (38).

Certain patients, particularly adult allogeneic recipients, might also experience chronic GVHD, which is graded as either limited or extensive chronic GVHD (19,39). Chronic GVHD appears similar to autoimmune, connective-tissue disorders (e.g., scleroderma or systemic lupus erythematosus) (40) and is associated with cellular and humoral immunodeficiencies, including macrophage deficiency, impaired neutrophil chemotaxis (41), poor response to vaccination (42--44), and severe mucositis (19). Risk factors for chronic GVHD include increasing age, allogeneic HSCT (particularly those among whom the donor is unrelated or a non-HLA identical family member) (40), and a history of acute GVHD (24,45). Chronic GVHD was first described as occurring >100 days after HSCT but can occur 40 days after HSCT (19). Although allogeneic recipients with chronic GVHD have normal or high total serum immunoglobulin levels (41), they experience long-lasting IgA, IgG, and IgG subclass deficiencies (41,46,47) and poor opsonization and impaired reticuloendothelial function. Consequently, they are at even greater risk for infections (32,39), particularly life-threatening bacterial infections from encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis). After chronic GVHD resolves, which might take years, cell-mediated and humoral immunity function are gradually restored.

HSCT recipients experience certain infections at different times posttransplant, reflecting the predominant host-defense defect(s) (Figure). Immune system recovery for HSCT recipients takes place in three phases beginning at day 0, the day of transplant. Phase I is the preengraftment phase (<30 days after HSCT); phase II, the postengraftment phase (30--100 days after HSCT); and phase III, the late phase (>100 days after HSCT). Prevention strategies should be based on these three phases and the following information:

Preventing infections among HSCT recipients is preferable to treating infections. How ever, despite recent technologic advances, more research is needed to optimize health outcomes for HSCT recipients. Efforts to improve immune system reconstitution, particularly among allogeneic transplant recipients, and to prevent or resolve the immune dysregulation resulting from donor-recipient histoincompatibility and GVHD remain substantial challenges for preventing recurrent, persistent, or progressive infections among HSCT patients.

Preventing Exposure

Because bacteria are carried on the hands, health-care workers (HCWs) and others in contact with HSCT recipients should routinely follow appropriate hand-washing practices to avoid exposing recipients to bacterial pathogens (AIII).

Preventing Disease

Preventing Early Disease (0--100 Days After HSCT). Routine gut decontamination is not recommended for HSCT candidates (51--53) (DIII). Because of limited data, no recommendations can be made regarding the routine use of antibiotics for bacterial prophylaxis among afebrile, asymptomatic neutropenic recipients. Although studies have reported that using prophylactic antibiotics might reduce bacteremia rates after HSCT (51), infection-related fatality rates are not reduced (52). If physicians choose to use prophylactic antibiotics among asymptomatic, afebrile, neutropenic recipients, they should routinely review hospital and HSCT center antibiotic-susceptibility profiles, particularly when using a single antibiotic for antibacterial prophylaxis (BIII). The emergence of fluoquinolone-resistant coagulase-negative Staphylococci and Es. coli (51,52), vancomycin-intermediate Sta. aureus and vancomycin-resistant Enterococcus (VRE) are increasing concerns (54). Vancomycin should not be used as an agent for routine bacterial prophylaxis (DIII). Growth factors (e.g., GM-CSF and G-CSF) shorten the duration of neutropenia after HSCT (55); however, no data were found that indicate whether growth factors effectively reduce the attack rate of invasive bacterial disease.

Physicians should not routinely administer IVIG products to HSCT recipients for bacterial infection prophylaxis (DII), although IVIG has been recommended for use in producing immune system modulation for GVHD prevention. Researchers have recommended routine IVIG*** use to prevent bacterial infections among the approximately 20%--25% of HSCT recipients with unrelated marrow grafts who experience severe hypogamma-globulinemia (e.g., IgG < 400 mg/dl) within the first 100 days after transplant (CIII). For example, recipients who are hypogammaglobulinemic might receive prophylactic IVIG to prevent bacterial sinopulmonary infections (e.g., from Stre. pneumoniae) (8) (CIII). For hypogammaglobulinemic allogeneic recipients, physicians can use a higher and more frequent dose of IVIG than is standard for non-HSCT recipients because the IVIG half-life among HSCT recipients (generally 1--10 days) is much shorter than the half-life among healthy adults (generally 18--23 days) (56--58). Additionally, infections might accelerate IgG catabolism; therefore, the IVIG dose for a hypogammaglobulinemic recipient should be individualized to maintain trough serum IgG concentrations >400--500 mg/dl (58) (BII). Consequently, physicians should monitor trough serum IgG concentrations among these patients approximately every 2 weeks and adjust IVIG doses as needed (BIII) (Appendix).

Preventing Late Disease (>100 Days After HSCT). Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic resistance patterns. In the absence of severe demonstrable hypogammaglobulinemia (e.g., IgG levels < 400 mg/dl, which might be associated with recurrent sinopulmonary infections), routine monthly IVIG administration to HSCT recipients >90 days after HSCT is not recommended (60) (DI) as a means of preventing bacterial infections.

Other Disease Prevention Recommendations. Routine use of IVIG among autologous recipients is not recommended (61) (DII). Recommendations for preventing bacterial infections are the same among pediatric or adult HSCT recipients.

Preventing Exposure

Appropriate care precautions should be taken with hospitalized patients infected with Stre. pneumoniae (62,63) (BIII) to prevent exposure among HSCT recipients.

Preventing Disease

Information regarding the currently available 23-valent pneumococcal polysaccharide vaccine indicates limited immunogenicity among HSCT recipients. However, because of its potential benefit to certain patients, it should be administered to HSCT recipients at 12 and 24 months after HSCT (64--66) (BIII). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, and Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Trimethoprim-sulfamethasaxole (TMP-SMZ) administered for Pneumocystis carinii pneumonia (PCP) prophylaxis will also provide protection against pneumococcal infections. However, no data were found to support using TMP-SMZ prophylaxis among HSCT recipients solely for the purpose of preventing Stre. pneumoniae disease. Certain strains of Stre. pneumoniae are resistant to TMP-SMZ and penicillin. Recommendations for preventing pneumococcal infections are the same for allogeneic or autologous recipients.

As with adults, pediatric HSCT recipients aged >2 years should be administered the current 23-valent pneumococcal polysaccharide vaccine because the vaccine can be effective (BIII). However, this vaccine should not be administered to children aged <2 years because it is not effective among that age population (DI). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among pediatric HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Preventing Exposure

Because Streptococci viridans colonize the oropharynx and gut, no effective method of preventing exposure is known.

Preventing Disease

Chemotherapy-induced oral mucositis is a potential source of Streptococci viridans bacteremia. Consequently, before conditioning starts, dental consults should be obtained for all HSCT candidates to assess their state of oral health and to perform any needed dental procedures to decrease the risk for oral infections after transplant (67) (AIII).

Generally, HSCT physicians should not use prophylactic antibiotics to prevent Streptococci viridans infections (DIII). No data were found that demonstrate efficacy of prophylactic antibiotics for this infection. Furthermore, such use might select antibiotic-resistant bacteria, and in fact, penicillin- and vancomycin-resistant strains of Streptococci viridans have been reported (68). However, when Streptococci viridans infections among HSCT recipients are virulent and associated with overwhelming sepsis and shock in an institution, prophylaxis might be evaluated (CIII). Decisions regarding the use of Streptococci viridans prophylaxis should be made only after consultation with the hospital epidemiologists or infection-control practitioners who monitor rates of nosocomial bacteremia and bacterial susceptibility (BIII).

HSCT physicians should be familiar with current antibiotic susceptibilities for patient isolates from their HSCT centers, including Streptococci viridans (BIII). Physicians should maintain a high index of suspicion for this infection among HSCT recipients with symptomatic mucositis because early diagnosis and aggressive therapy are currently the only potential means of preventing shock when severely neutropenic HSCT recipients experience Streptococci viridans bacteremia (69).

Preventing Exposure

Adults with Ha. influenzae type b (Hib) pneumonia require standard precautions (62) to prevent exposing the HSCT recipient to Hib. Adults and children who are in contact with the HSCT recipient and who have known or suspected invasive Hib disease, including meningitis, bacteremia, or epiglottitis, should be placed in droplet precautions until 24 hours after they begin appropriate antibiotic therapy, after which they can be switched to standard precautions. Household contacts exposed to persons with Hib disease and who also have contact with HSCT recipients should be administered rifampin prophylaxis according to published recommendations (70,71); prophylaxis for household contacts of a patient with Hib disease are necessary if all contacts aged <4 years are not fully vaccinated (BIII) (Appendix). This recommendation is critical because the risk for invasive Hib disease among unvaccinated household contacts aged <4 years is increased, and rifampin can be effective in eliminating Hib carriage and preventing invasive Hib disease (72--74). Pediatric household contacts should be up-to-date with Hib vaccinations to prevent possible Hib exposure to the HSCT recipient (AII).

Preventing Disease

Although no data regarding vaccine efficacy among HSCT recipients were found, Hib conjugate vaccine should be administered to HSCT recipients at 12, 14, and 24 months after HSCT (BII). This vaccine is recommended because the majority of HSCT recipients have low levels of Hib capsular polysaccharide antibodies >4 months after HSCT (75), and allogeneic recipients with chronic GVHD are at increased risk for infection from encapsulated organisms (e.g., Hib) (76,77). HSCT recipients who are exposed to persons with Hib disease should be offered rifampin prophylaxis according to published recommendations (70) (BIII) (Appendix).

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic-resistance patterns. Recommendations for preventing Hib infections are the same for allogeneic or autologous recipients. Recommendations for preventing Hib disease are the same for pediatric or adult HSCT recipients, except that any child infected with Hib pneumonia requires standard precautions with droplet precautions added for the first 24 hours after beginning appropriate antibiotic therapy (62,70) (BIII). Appropriate pediatric doses should be administered for Hib conjugate vaccine and for rifampin prophylaxis (71) (Appendix).

Preventing Exposure

HSCT candidates should be tested for the presence of serum anti-CMV IgG antibodies before transplantation to determine their risk for primary CMV infection and reactivation after HSCT (AIII). Only Food and Drug Administration (FDA) licensed or approved tests should be used. HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others, including family members, to decrease the risk for CMV exposure (BIII).

Sexually active patients who are not in long-term monogamous relationships should always use latex condoms during sexual contact to reduce their risk for exposure to CMV and other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for CMV infections. Therefore, during periods of immuno-compromise, sexually active HSCT recipients in monogamous relationships should ask partners to be tested for serum CMV IgG antibody, and discordant couples should use latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII).

After handling or changing diapers or after wiping oral and nasal secretions, HSCT candidates and recipients should practice regular hand washing to reduce the risk for CMV exposure (AII). CMV-seronegative recipients of allogeneic stem cell transplants from CMV-seronegative donors (i.e., R-negative or D-negative) should receive only leukocyte-reduced or CMV-seronegative red cells or leukocyte-reduced platelets (<1 x 106 leukocytes/unit) to prevent transfusion-associated CMV infection (78) (AI). However, insufficient data were found to recommend use of leukocyte-reduced or CMV-seronega tive red cells and platelets among CMV-seronegative recipients who have CMV-seropositive donors (i.e., R-negative or D-positive).

All HCWs should wear gloves when handling blood products or other potentially contaminated biologic materials (AII) to prevent transmission of CMV to HSCT recipients. HSCT patients who are known to excrete CMV should be placed under standard precautions (62) for the duration of CMV excretion to avoid possible transmission to CMV-seronegative HSCT recipients and candidates (AIII). Physicians are cautioned that CMV excretion can be episodic or prolonged.

Preventing Disease and Disease Recurrence

HSCT recipients at risk for CMV disease after HSCT (i.e., all CMV-seropositive HSCT recipients, and all CMV-seronegative recipients with a CMV-seropositive donor) should be placed on a CMV disease prevention program from the time of engraftment until 100 days after HSCT (i.e., phase II) (AI). Physicians should use either prophylaxis or preemptive treatment with ganciclovir for allogeneic recipients (AI). In selecting a CMV disease prevention strategy, physicians should assess the risks and benefits of each strategy, the needs and condition of the patient, and the hospital's virology laboratory support capability.

Prophylaxis strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients involves administering ganciclovir prophylaxis to all allogeneic recipients at risk throughout phase II (i.e., from engraftment to 100 days after HSCT). The induction course is usually started at engraftment (AI), although physicians can add a brief prophylactic course during HSCT preconditioning (CIII) (Appendix).

Preemptive strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients is preferred over prophylaxis for CMV-seronegative HSCT recipients of seropositive donor cells (i.e., D-positive or R-negative) because of the low attack rate of active CMV infection if screened or filtered blood product support is used (BII). Preemptive strategy restricts ganciclovir use for those patients who have evidence of CMV infection after HSCT. It requires the use of sensitive and specific laboratory tests to rapidly diagnose CMV infection after HSCT and to enable immediate administration of ganciclovir after CMV infection has been detected. Allogeneic recipients at risk should be screened >1 times/week from 10 days to 100 days after HSCT (i.e., phase II) for the presence of CMV viremia or antigenemia (AIII).

HSCT physicians should select one of two diagnostic tests to determine the need for preemptive treatment. Currently, the detection of CMV pp65 antigen in leukocytes (antigenemia) (79,80) is preferred for screening for preemptive treatment because it is more rapid and sensitive than culture and has good positive predictive value (79--81). Direct detection of CMV-DNA (deoxyribonucleic acid) by polymerase chain reaction (PCR) (82) is very sensitive but has a low positive predictive value (79). Although CMV-DNA PCR is less sensitive than whole blood or leukocyte PCR, plasma CMV-DNA PCR is useful during neutropenia, when the number of leukocytes/slide is too low to allow CMV pp65 antigenemia testing.

Virus culture of urine, saliva, blood, or bronchoalveolar washings by rapid shell-vial culture (83) or routine culture (84,85) can be used; however, viral culture techniques are less sensitive than CMV-DNA PCR or CMV pp65 antigenemia tests. Also, rapid shell-viral cultures require >48 hours and routine viral cultures can require weeks to obtain final results. Thus, viral culture techniques are less satisfactory than PCR or antigenemia tests. HSCT centers without access to PCR or antigenemia tests should use prophylaxis rather than preemptive therapy for CMV disease prevention (86) (BII). Physicians do use other diagnostic tests (e.g., hybrid capture CMV-DNA assay, Version 2.0 [87] or CMV pp67 viral RNA [ribonucleic acid] detection) (88); however, limited data were found regarding use among HSCT recipients, and therefore, no recommendation for use can be made.

Allogeneic recipients <100 days after HSCT (i.e., during phase II) should begin preemptive treatment with ganciclovir if CMV viremia or any antigenemia is detected or if the recipient has >2 consecutively positive CMV-DNA PCR tests (BIII). After preemptive treatment has been started, maintenance ganciclovir is usually continued until 100 days after HSCT or for a minimum of 3 weeks, whichever is longer (AI) (Appendix). Antigen or PCR tests should be negative when ganciclovir is stopped. Studies report that a shorter course of ganciclovir (e.g., for 3 weeks or until negative PCR or antigenemia occurs) (89--91) might provide adequate CMV prevention with less toxicity, but routine weekly screening by pp65 antigen or PCR test is necessary after stopping ganciclovir because CMV reactivation can occur (BIII).

Presently, only the intravenous formulation of ganciclovir has been approved for use in CMV prophylactic or preemptive strategies (BIII). No recommendation for oral ganciclovir use among HSCT recipients can be made because clinical trials evaluating its efficacy are still in progress. One group has used ganciclovir and foscarnet on alternate days for CMV prevention (92), but no recommendation can be made regarding this strategy because of limited data. Patients who are ganciclovir-intolerant should be administered foscarnet instead (93) (BII) (Appendix). HSCT recipients receiving ganciclovir should have ANCs checked >2 times/week (BIII). Researchers report managing ganciclovir-associated neutropenia by adding G-CSF (94) or temporarily stopping ganciclovir for >2 days if the patient's ANC is <1,000 (CIII). Ganciclovir can be restarted when the patient's ANC is >1,000 for 2 consecutive days. Alternatively, researchers report substituting foscarnet for ganciclovir if a) the HSCT recipient is still CMV viremic or antigenemic or b) the ANC remains <1,000 for >5 days after ganciclovir has been stopped (CIII) (Appendix). Because neutropenia accompanying ganciclovir administration is usually brief, such patients do not require antifungal or antibacterial prophylaxis (DIII).

Currently, no benefit has been reported from routinely administering ganciclovir prophylaxis to all HSCT recipients at >100 days after HSCT (i.e., during phase III). However, persons with high risk for late CMV disease should be routinely screened biweekly for evidence of CMV reactivation as long as substantial immunocompromise persists (BIII). Risk factors for late CMV disease include allogeneic HSCT accompanied by chronic GVHD, steroid use, low CD4 counts, delay in high avidity anti-CMV antibody, and recipients of matched unrelated or T-cell--depleted HSCTs who are at high risk (95--99). If CMV is still detectable by routine screening >100 days after HSCT, ganciclovir should be continued until CMV is no longer detectable (AI). If low-grade CMV antigenemia (<5 positive cells/slide) is detected on routine screening, the antigenemia test should be repeated in 3 days (BIII). If CMV antigenemia indicates >5 cells/slide, PCR is positive, or the shell-vial culture detects CMV viremia, a 3-week course of preemptive ganciclovir treatment should be administered (BIII) (Appendix). Ganciclovir should also be started if the patient has had >2 consecutively positive viremia or PCR tests (e.g., in a person receiving steroids for GVHD or who received ganciclovir or foscarnet at <100 days after HSCT). Current investigational strategies for preventing late CMV disease include the use of targeted prophylaxis with antiviral drugs and cellular immunotherapy for those with deficient or absent CMV-specific immune system function.

If viremia persists after 4 weeks of ganciclovir preemptive therapy or if the level of antigenemia continues to rise after 3 weeks of therapy, ganciclovir-resistant CMV should be suspected. If CMV viremia recurs during continuous treatment with ganciclovir, researchers report restarting ganciclovir induction (100) or stopping ganciclovir and starting foscarnet (CIII). Limited data were found regarding the use of foscarnet among HSCT recipients for either CMV prophylaxis or preemptive therapy (92,93).

Infusion of donor-derived CMV-specific clones of CD8+ T-cells into the transplant recipient is being evaluated under FDA Investigational New Drug authorization; therefore, no recommendation can be made. Although, in a substantial cooperative study, high-dose acyclovir has had certain efficacy for preventing CMV disease (101), its utility is limited in a setting where more potent anti-CMV agents (e.g., ganciclovir) are used (102). Acyclovir is not effective in preventing CMV disease after autologous HSCT (103) and is, therefore, not recommended for CMV preemptive therapy (DII). Consequently, valacyclovir, although under study for use among HSCT recipients, is presumed to be less effective than ganciclovir against CMV and is currently not recommended for CMV disease prevention (DII).

Although HSCT physicians continue to use IVIG for immune system modulation, IVIG is not recommended for CMV disease prophylaxis among HSCT recipients (DI). Cidofovir, a nucleoside analog, is approved by FDA for the treatment of AIDS-associated CMV retinitis. The drug's major disadvantage is nephrotoxicity. Cidofovir is currently in FDA phase 1 trial for use among HSCT recipients; therefore, recommendations for its use cannot be made.

Use of CMV-negative or leukocyte-reduced blood products is not routinely required for all autologous recipients because most have a substantially lower risk for CMV disease. However, CMV-negative or leukocyte-reduced blood products can be used for CMV-seronegative autologous recipients (CIII). Researchers report that CMV-seropositive autologous recipients be evaluated for preemptive therapy if they have underlying hematologic malignancies (e.g., lymphoma or leukemia), are receiving intense conditioning regimens or graft manipulation, or have recently received fludarabine or 2-chlorodeoxyadenosine (CDA) (CIII). This subpopulation of autologous recipients should be monitored weekly from time of engraftment until 60 days after HSCT for CMV reactivation, preferably with quantitative CMV pp65 antigen (80) or quantitative PCR (BII).

Autologous recipients at high risk who experience CMV antigenemia (i.e., blood levels of >5 positive cells/slide) should receive 3 weeks of preemptive treatment with ganciclovir or foscarnet (80), but CD34+-selected patients should be treated at any level of antigenemia (BII) (Appendix). Prophylactic approach to CMV disease prevention is not appropriate for CMV-seropositive autologous recipients. Indications for the use of CMV prophylaxis or preemptive treatment are the same for children or adults.

Preventing Exposure

All transplant candidates, particularly those who are EBV-seronegative, should be advised of behaviors that could decrease the likelihood of EBV exposure (AII). For example, HSCT recipients and candidates should follow safe hygiene practices (e.g., frequent hand washing [AIII] and avoiding the sharing of cups, glasses, and eating utensils with others) (104) (BIII), and they should avoid contact with potentially infected respiratory secretions and saliva (104) (AII).

Preventing Disease

Infusion of donor-derived, EBV-specific cytotoxic T-lymphocytes has demonstrated promise in the prophylaxis of EBV-lymphoma among recipients of T-cell--depleted unrelated or mismatched allogeneic recipients (105,106). However, insufficient data were found to recommend its use. Prophylaxis or preemptive therapy with acyclovir is not recommended because of lack of efficacy (107,108) (DII).

Preventing Exposure

HSCT candidates should be tested for serum anti-HSV IgG before transplant (AIII); however, type-specific anti-HSV IgG serology testing is not necessary. Only FDA-licensed or -approved tests should be used. All HSCT candidates, particularly those who are HSV-seronegative, should be informed of the importance of avoiding HSV infection while immunocompromised and should be advised of behaviors that will decrease the likelihood of HSV exposure (AII). HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others (BIII). Sexually active patients who are not in a long-term monogamous relationship should always use latex condoms during sexual contact to reduce the risk for exposure to HSV as well as other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for HSV infections. Therefore, during periods of immunocompromise, sexually active HSCT recipients in such relationships should ask partners to be tested for serum HSV IgG antibody. If the partners are discordant, they should consider using latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII). Any person with disseminated, primary, or severe mucocutaneous HSV disease should be placed under contact precautions for the duration of the illness (62) (AI) to prevent transmission of HSV to HSCT recipients.

Preventing Disease and Disease Recurrence

Acyclovir. Acyclovir prophylaxis should be offered to all HSV-seropositive allogeneic recipients to prevent HSV reactivation during the early posttransplant period (109--113) (AI). Standard approach is to begin acyclovir prophylaxis at the start of the conditioning therapy and continue until engraftment occurs or until mucositis resolves, whichever is longer, or approximately 30 days after HSCT (BIII) (Appendix). Without supportive data from controlled studies, routine use of antiviral prophylaxis for >30 days after HSCT to prevent HSV is not recommended (DIII). Routine acyclovir prophylaxis is not indicated for HSV-seronegative HSCT recipients, even if the donors are HSV-seropositive (DIII). Researchers have proposed administration of ganciclovir prophylaxis alone (86) to HSCT recipients who required simultaneous prophylaxis for CMV and HSV after HSCT (CIII) because ganciclovir has in vitro activity against CMV and HSV 1 and 2 (114), although ganciclovir has not been approved for use against HSV.

Valacyclovir. Researchers have reported valacyclovir use for preventing HSV among HSCT recipients (CIII); however, preliminary data demonstrate that very high doses of valacyclovir (8 g/day) were associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome among HSCT recipients (115). Controlled trial data among HSCT recipients are limited (115), and the FDA has not approved valacyclovir for use among recipients. Physicians wishing to use valacyclovir among recipients with renal impairment should exercise caution and decrease doses as needed (BIII) (Appendix).

Foscarnet. Because of its substantial renal and infusion-related toxicity, foscarnet is not recommended for routine HSV prophylaxis among HSCT recipients (DIII).

Famciclovir. Presently, data regarding safety and efficacy of famciclovir among HSCT recipients are limited; therefore, no recommendations for HSV prophylaxis with famciclovir can be made.

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Guidelines for Preventing Opportunistic Infections Among ...

Skin Stem Cells Comments Off on Guidelines for Preventing Opportunistic Infections Among … | October 12th, 2016

9thInternational Conference on Hematology

Date: November 02-04, 2017

Venue: Las Vegas, USA

Hematology 2016 has been designed with many interesting and informative scientific sessions; it includes all possible aspects of Hematology research.

Hematology

Erythrocytesare also known as red blood cells which carry oxygen to the body and collect carbon dioxide from the body by the use of hemoglobin and its life span of 120 days. along the side the leucocytes helps in protecting the healthy cells because the W.B.C (leucocytes) act as the defending cells in protecting the immune system from the foreign cells. Theseleucocytesare multipotent cells in bone marrow and there life span is of 3-4 days where the yellow blood cells are called as thrombocytes they are where small and irregular in shape they have life span of 5-9 days they are mostly seen in mammals they help in clotting of blood which are in fibrin form called as thrombosis these lead to heart stroke, blockage of blood in blood mostly in arms and legs. where C.B.C is known ascomplete blood countis done to know the number of cells in a body these are mainly done by lab technician presently they are been tested by automatic analyzer the high and low amount of cells will lead to many diseases. Decrease of R.B.C in the body these causes of anemia which leads to weakness, feeling of tired, shortness of breath and person will be noticeably pale. Formation of blood cellular components are called as Hematopoiesis and all the cellular blood components are derived from hematopoiesis stem cells in a healthy individual nearly 10111012new blood cells are produced these help in steady peripheral circulation. If there is a increases of R.B.C in the body these causes polycythemia these can be measured through hematocrit level.

Blood Disorders

Hemophilia Ais a genetic deficiency in clottingfactor VIII,which causes increased bleeding and usually affects males. About 70% of the time it is inherited as an X-linked recessive trait, but around 30% of cases arise from spontaneous mutations. Hemophilia B is ablood clottingdisorder caused by amutationof thefactor IXgene, leading to a deficiency of factor IX. It is the second-most common form ofhaemophilia, rarer thanhaemophilia A. It is sometimes calledChristmas disease, named afterStephen Christmas, the first patient described with this disease.In addition, the first report of its identification was published in the Christmas edition of theBritish Medical Journal.Hemophilia C is a mild form of haemophiliaaffecting both sexes. However, it predominantly occurs in Jews ofAshkenazidescent. It is the fourth most common coagulationdisorder aftervon Willebrand's diseaseandhaemophiliaAandB.In theUSAit is thought to affect 1 in 100,000 of the adult population, making it 10% as common as haemophilia A. Idiopathic thrombocytopenic purpura(ITP), also known asimmune thrombocytopenia,primary immune thrombocytopenia,primary immune thrombocytopenic purpuraorautoimmune thrombocytopenic purpura, is defined as isolated low platelet count (thrombocytopenia) with normalbone marrowand the absence of other causes of thrombocytopeniaVon Willebrand diseasesis the most common hereditarycoagulationabnormality described in humans. Platelets also called "thrombocytes" areblood cellswhose function (along with thecoagulation factors) is to stop bleeding by clumping and clogging blood vessel injuries.Platelets have nocell nucleus: Coagulation is highlyconservedthroughout biology; in allmammals, coagulation involves both a cellular (platelet) and aprotein(coagulation factor) component and these are occoured due togenetic blood disorders

Hematologic Malignancies

Lymphatic leukemiawhich effect the white blood cells(w.b.c) they are closely related to the lymphomas and some of them are unitary diseases which related to the adult T cells leukemia these come under the lymphoproliferative disorders. Mostly they involve in the B-cell sub type lymphocytes. The myeloid leukemia is preferred to the granulocyte precursor in the bone marrow and spinal cord and these arises the abnormal growth in the blood from tissues in the bone marrow. They are mainly related to the hematopoietic cells and these sub title into acute and chronic lymphoblastic leukemia. The acute leukemia is that rapidly producing immature blood cells as they are bulk number of cells healthy cells are not produced in bone marrow due this spill over the blood stream which spread to other body parts. Where as in chronic leukemia highly bulid of matured cells are formed but still abnormal white cells are formed these can not be treated immediately mostly seen in older people. The cancer which originate from white blood cells are called as lymphoma and this disorder is mainly seen inHodgkin lymphomathese diseases is treated by radiation and chemotherapy, orhematopoietic stem cell transplantation. The cancer which starts with in the cell are called as Non Hodgkin lymphocytes and these lymphocytes are of lymph nodes. The bone marrow which develops too many white blood cells leads tomultiple myleoma. The further details on malignance are been discussed inHematology oncology conference-2015.

Hematology and immunology

Blood groupsare of ABO type and but at present the Rh blood grouping of 50 well defined antigens in which 5 are more important they are D,C,c,E and e and Rh factors are of Rh positive and Rh negative which refers to the D-antigen. These D-antigen helps in prevention of erythroblast fetalis lacking of Rh antigen it defined as negative and presences of Rh antigen in blood leads to positive these leads to rh incompatibility. The prevention treatment of diseases related to the blood is called as the Hematology. The hematologists conduct works on cancer to. The disorder of immune system leading to hypersensitivity is called asClinical Immunologyand the abnormal growth of an infection are known as Inflammation and the arise of an abnormal immune response to the body or an immune suppression are known as Auto immune disorder. The stem cell therapy is used to treat or prevent a disease or a condition mostly Bone marrow stem cell therapy is seen and recently umbilical cord therapy Stem cell transplantation strategies remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases.

Blood Transplantation

Theumbilical cordis a conduit between the developingembryoorfetusand theplacenta. The umbilical vein supplies the fetus with nutrient-richbloodfrom theplacenta The hematopoitic bone marrow transplant, the HSC are removed from a large bone of the donor, typically thepelvis, through a largeneedlethat reaches the center of the bone. Acute myeloid leukemia is a cancerof themyeloidline of blood cells, characterized by the rapid growth of abnormalwhite blood cellsthat accumulate in thebone marrowand interfere withthe production of normal blood cells and the Thrombosis is the formation of ablood clot inside ablood vessel, obstructing the flow ofbloodthrough thecirculatory system. TheHemostaticis a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel this is the first stage of wound healing. Metabolic syndromeis a disorder of energy utilization and storage, diagnosed by a co-occurrence of three out of five of the following medical conditions, obesity,elevated blood pressure,elevated fasting plasma glucose,high serum triglycerides, and lowhigh-density lipoprotein(HDL) levels. Metabolic syndrome increases the risk developingcardiovascular diseaseanddiabetes.

Diagnosis and Treatment

Palliative careis amultidisciplinary approachto specialisedmedical carefor people with seriousillnesses The spleen, similar in structure to a largelymph node, acts as a blood filter. Anticoagulants(antithrombics) are a class of drugs that work to prevent thecoagulation(clotting) of blood. Some anticoagulants are used in medical equipment, such astest tubes ,blood transfusionbags, andrenal dialysisequipment. Anvena cava filteris a type of vascular filter, amedicaldevice that is implanted byinterventional radiologistsor vascular surgeons into theinferior vena cavato presumably prevent life-threateningpulmonary emboliistherapyusingionizing radiation, generally as part of cancer treatmentto control or killmalignantcells. Radiation therapy may be curative in a number of types of cancer if they are localized to one area of the body. The subspecialty ofoncologythat focuses on radiotherapy is calledradiation oncology. Translational research is another term fortranslated researchandtranslational science, Applying knowledge from basic science is a major stumbling block in science, partially due to the compartmentalization within science. Targeted drug delivery is a method of deliveringmedicationto a patient in a manner that increases theconcentrationof the medication in some parts of the body relative to others.

New Drug Development in Haematology

The development of antibiotic resistance in particular stems from the drugs targeting only specific bacterial molecules. Because the drugisso specific, any mutation in these molecules will interfere with or negate its destructive effect, resulting in antibiotic resistance. Known asDrug deliveryConditions treated with combination therapy includetuberculosis,leprosy,cancer,malaria, andHIV/AIDS. One major benefit of combination therapies is that they reduce development ofdrug resistance, since a pathogen or tumor is less likely to have resistance to multiple drugs simultaneously.Artemisinin-based monotherapies for malaria are explicitly discouraged to avoid the problem of developing resistance to the newer treatment. Drug Induced Blood Disorders causes of sickle cell anemia,pale skin non steroids antiinflammatory drugswhich causes ulcers Using drug repositioning, pharmaceutical companies have achieved a number successes, for examplePfizer'sViagrainerectile dysfunctionandCelgene'sthalidomidein severe erythema nodosum leprosum. Smaller companies, including Ore Pharmaceuticals,Biovista, Numedicus,Melior Discoveryand SOM Biotech are also performing drug repositioning on a systematic basis. These companies use a combination of approaches including in silico biology and in vivo/in vitro experimentation to assess a compound and develop and confirm hypotheses concerning its usage for new indications.

Hematology Research

Lymphatic diseasesthis is a type of cancer of the lymphatic system. It can start almost any where in the body. It's believed to be caused by HIV, Epstein-Barr Syndrome, age and family history. Symptoms include weight loss, fever, swollen lymph nodes, night sweats, itchy skin, fatigue, chest pain, coughing and/or trouble swallowing. Thelymphatic systemis part of thecirculatory system, comprising a network oflymphatic vesselsthat carry a clear fluid called lymph directionally towards the heart. The lymphatic system was first described in the seventeenth century independently byOlaus RudbeckandThomas Bartholin. Unlike thecardiovascular systemthe lymphatic system is not a closed system. The human circulatory system processes an average of 20 litres ofbloodper day throughcapillary filtrationwhich removesplasmawhile leaving theblood cells. Roughly 17 litres of the filtered plasma get reabsorbed directly into the blood vessels, while the remaining 3 litres are left behind in theinterstitial fluid. One of the main functions of the lymph system is to provide an accessory return route to the blood for the surplus 3 litres. Lymphatic diseases are ofNon-Hodgkin's Lymphoma, Hodgkins. Thethymusis a specialized primarylymphoidorgan of theimmune system. Within the thymus,T cellsor Tlymphocytesmature. T cells are critical to theadaptive immune system, where the body adapts specifically to foreign invaders.One of the example of lymph node development. Formation oflymph nodeinto the tumor which lead to cancer called oncology.

Various Aspects of Haematology

Pediatric Haematology and Oncologyis an internationalpeer-reviewedmedical journalthat covers all aspects ofpediatrichematologyandoncology. The journal covers immunology, pathology, and pharmacology in relation to blood diseases and cancer in children and shows how basic experimental research can contribute to the understanding of clinical problems. Physicians specialized in hematology are known ashematologistsorhaematologists. Their routine work mainly includes the care and treatment of patients with hematological diseases, although some may also work at the hematology laboratory viewingblood filmsandbone marrowslides under themicroscope, interpreting various hematological test results andblood clotting testresults. In some institutions, hematologists also manage the hematology laboratory. Physicians who work in hematology laboratories, and most commonly manage them, are pathologists specialized in the diagnosis of hematological diseases, referred to as hematopathologistsorhaematopathologists.Experimental Hematologyis apeer-reviewedmedical journalofhematology, which publishesoriginal researcharticles and reviews, as well as the abstracts of the annual proceedings of theSociety for Hematology and Stem Cells and they should be done under theHematology guidlines.

Blood Based Products

Ablood substituteis a substance used to mimic and fulfill some functions ofbiologicalblood. It aims to provide an alternative toblood transfusion, which is transferring blood orblood-based productsfrom one person into another. Thus far, there are no well-acceptedoxygen-carryingblood substitutes, which is the typical objective of ared blood celltransfusion; however, there are widely available non-bloodvolume expandersfor cases where only volume restoration is required. These are helping doctors and surgeons avoid the risks of disease transmission and immune suppression, address the chronic blood donor shortage, and address the concerns of Jehovah's Witnesses and others who have religious objections to receiving transfused blood.Pathogen reductionusing riboflavin and UV lightis a method by which infectiouspathogensinblood for transfusionare inactivated by addingriboflavinand irradiating withUV light. This method reduces the infectious levels of disease-causing agents that may be found in donated blood components, while still maintaining good quality blood components for transfusion. This type of approach to increase blood safety is also known as pathogen inactivation in the industry. Anartificial cellorminimal cellis an engineered particle that mimics one or many functions of abiological cell. The term does not refer to a specific physical entity, but rather to the idea that certain functions or structures of biological cells can be replaced or supplemented with a synthetic entity. Often, artificial cells are biological or polymeric membranes which enclose biologically active materials. As such,nanoparticles,liposomes,polymersomes, microcapsules and a number of other particles have qualified as artificial cells.Manufacturing of semi synthetic products of drugs are known as therapeutic biological products.Anticoagulants(antithrombics) are a class of drugs that work to prevent thecoagulation(clotting) of blood. Such substances occur naturally in leeches and blood-sucking insects.

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Hematology Conferences | Blood Disorder Conferences | USA ...

Cardiac Stem Cells Comments Off on Hematology Conferences | Blood Disorder Conferences | USA … | October 9th, 2016

Some cells are visible to the unaided eye

The smallest objects that the unaided human eye can see are about 0.1 mm long. That means that under the right conditions, you might be able to see an ameoba proteus, a human egg, and a paramecium without using magnification. A magnifying glass can help you to see them more clearly, but they will still look tiny.

Smaller cells are easily visible under a light microscope. It's even possible to make out structures within the cell, such as the nucleus, mitochondria and chloroplasts. Light microscopes use a system of lenses to magnify an image. The power of a light microscope is limited by the wavelength of visible light, which is about 500 nm. The most powerful light microscopes can resolve bacteria but not viruses.

To see anything smaller than 500 nm, you will need an electron microscope. Electron microscopes shoot a high-voltage beam of electrons onto or through an object, which deflects and absorbs some of the electrons. Resolution is still limited by the wavelength of the electron beam, but this wavelength is much smaller than that of visible light. The most powerful electron microscopes can resolve molecules and even individual atoms.

The label on the nucleotide is not quite accurate. Adenine refers to a portion of the molecule, the nitrogenous base. It would be more accurate to label the nucleotide deoxyadenosine monophosphate, as it includes the sugar deoxyribose and a phosphate group in addition to the nitrogenous base. However, the more familiar "adenine" label makes it easier for people to recognize it as one of the building blocks of DNA.

No, this isn't a mistake. First, there's less DNA in a sperm cell than there is in a non-reproductive cell such as a skin cell. Second, the DNA in a sperm cell is super-condensed and compacted into a highly dense form. Third, the head of a sperm cell is almost all nucleus. Most of the cytoplasm has been squeezed out in order to make the sperm an efficient torpedo-like swimming machine.

The X chromosome is shown here in a condensed state, as it would appear in a cell that's going through mitosis. It has also been duplicated, so there are actually two identical copies stuck together at their middles. A human sperm cell contains just one copy each of 23 chromosomes.

A chromosome is made up of genetic material (one long piece of DNA) wrapped around structural support proteins (histones). Histones organize the DNA and keep it from getting tangled, much like thread wrapped around a spool. But they also add a lot of bulk. In a sperm cell, a specialized set of tiny support proteins (protamines) pack the DNA down to about one-sixth the volume of a mitotic chromosome.

The size of the carbon atom is based on its van der Waals radius.

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Cell Size and Scale - Learn Genetics

Skin Stem Cells Comments Off on Cell Size and Scale – Learn Genetics | October 7th, 2016

Open Access

Article

The Arabidopsis CERK1associated kinase PBL27 connects chitin perception to MAPK activation

These authors contributed equally to this work as first authors

These authors contributed equally to this work as third authors

Chitin receptor CERK1 transmits immune signals to the intracellular MAPK cascade in plants. This occurs via phosphorylation of MAPKKK5 by the CERK1associated kinase PBL27, providing a missing link between pathogen perception and signaling output.

Chitin receptor CERK1 transmits immune signals to the intracellular MAPK cascade in plants. This occurs via phosphorylation of MAPKKK5 by the CERK1associated kinase PBL27, providing a missing link between pathogen perception and signaling output.

CERK1associated kinase PBL27 interacts with MAPKKK5 at the plasma membrane.

Chitin perception induces disassociation of PBL27 and MAPKKK5.

PBL27 functions as a MAPKKK kinase.

Phosphorylation of MAPKKK5 by PBL27 is enhanced upon phosphorylation of PBL27 by CERK1.

Phosphorylation of MAPKKK5 by PBL27 is required for chitininduced MAPK activation in planta.

Kenta Yamada, Koji Yamaguchi, Tomomi Shirakawa, Hirofumi Nakagami, Akira Mine, Kazuya Ishikawa, Masayuki Fujiwara, Mari Narusaka, Yoshihiro Narusaka, Kazuya Ichimura, Yuka Kobayashi, Hidenori Matsui, Yuko Nomura, Mika Nomoto, Yasuomi Tada, Yoichiro Fukao, Tamo Fukamizo, Kenichi Tsuda, Ken Shirasu, Naoto Shibuya, Tsutomu Kawasaki

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Home | The EMBO Journal

Skin Stem Cells Comments Off on Home | The EMBO Journal | October 6th, 2016

Do you ever wonder what makes up blood? Unless you need to have blood drawn, donate it or have to stop its flow after an injury, you probably don't think much about it. But blood is the most commonly tested part of the body, and it is truly the river of life. Every cell in the body gets its nutrients from blood. Understanding blood will help you as your doctor explains the results of your blood tests. In addition, you will learn amazing things about this incredible fluid and the cells in it.

Blood is a mixture of two components: cells and plasma. The heart pumps blood through the arteries, capillaries and veins to provide oxygen and nutrients to every cell of the body. The blood also carries away waste products.

The adult human body contains approximately 5 liters (5.3 quarts) of blood; it makes up 7 to 8 percent of a person's body weight. Approximately 2.75 to 3 liters of blood is plasma and the rest is the cellular portion.

Plasma is the liquid portion of the blood. Blood cells like red blood cells float in the plasma. Also dissolved in plasma are electrolytes, nutrients and vitamins (absorbed from the intestines or produced by the body), hormones, clotting factors, and proteins such as albumin and immunoglobulins (antibodies to fight infection). Plasma distributes the substances it contains as it circulates throughout the body.

The cellular portion of blood contains red blood cells (RBCs), white blood cells (WBCs) and platelets. The RBCs carry oxygen from the lungs; the WBCs help to fight infection; and platelets are parts of cells that the body uses for clotting. All blood cells are produced in the bone marrow. As children, most of our bones produce blood. As we age this gradually diminishes to just the bones of the spine (vertebrae), breastbone (sternum), ribs, pelvis and small parts of the upper arm and leg. Bone marrow that actively produces blood cells is called red marrow, and bone marrow that no longer produces blood cells is called yellow marrow. The process by which the body produces blood is called hematopoiesis. All blood cells (RBCs, WBCs and platelets) come from the same type of cell, called the pluripotential hematopoietic stem cell. This group of cells has the potential to form any of the different types of blood cells and also to reproduce itself. This cell then forms committed stem cells that will form specific types of blood cells.

We'll learn more about red blood cells in detail next.

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How Blood Works | HowStuffWorks

Skin Stem Cells Comments Off on How Blood Works | HowStuffWorks | October 5th, 2016

The 5th International Conference on Tissue Engineering & Regenerative Medicine which is going to be held during September 12-14, 2016 at Berlin, Germany will bring together world-class personalities working on stem cells, tissue engineering and regenerative medicine to discuss materials-related strategies for disease remediation and tissue repair.

Tissue Regeneration

In the field of biology, regeneration is the progression of renewal, regeneration and growth that makes it possible for genomes, cells, organ regeneration to natural changes or events that cause damage or disturbance.This study is carried out as craniofacial tissue engineering, in-situtissue regeneration, adipose-derived stem cells for regenerative medicine which is also a breakthrough in cell culture technology. The study is not stopped with the regeneration of tissue where it is further carried out in relation with cell signaling, morphogenetic proteins. Most of the neurological disorders occurred accidental having a scope of recovery by replacement or repair of intervertebral discs repair, spinal fusion and many more advancements. The global market for tissue engineering and regeneration products such as scaffolds, tissueimplants, biomimetic materials reached $55.9 billion in 2010 and it is expected to reach $89.7 billion by 2016 at a compounded annual growth rate (CAGR) of 8.4%. It grows to $135 billion by 2024.

Related Conferences

5th InternationalConference on Tissue Engineering and Regenerative Medicine September 12-14, 2016 Berlin, Germany; 5th International Conference onCell and Gene Therapy May 19-21, 2016 San Antonio, USA; InternationalConference on Cancer Immunologyand ImmunotherapyJuly 28-30, 2016 Melbourne, Australia; InternationalConference on Molecular BiologyOctober 13-15, 2016 Dubai, UAE; Tissue Niches and Resident Stem Cells in Adult Epithelia Gordon Research Conference, Regulation of Tissue Homeostasis by Signalling in the Stem Cell Niche August 7-12, Hong Kong, China; 10 Years of IPSCs, Cell Symposia, September 25-27, 2016 Berkeley, CA, USA; World Stem Cells and Regenerative Medicine Congress May 18-20, 2016 London, UK; Notch Signaling in Development, Regeneration and Disease Gordon Research Conference, July 31-August 5, 2016 Lewiston, ME, USA

Designs for Tissue Engineering

The developing field of tissue engineering aims to regenerate damaged tissues by combining cells from the body withbioresorbablematerials, biodegradable hydrogel, biomimetic materials, nanostructures andnanomaterials, biomaterials and tissue implants which act as templates for tissue regeneration, to guide the growth of new tissue by using with the technologies. The global market for biomaterials, nanostructures and bioresorbable materials are estimated to reach $88.4 billion by 2017 from $44.0 billion in 2012 growing at a CAGR of 15%. Further the biomaterials market estimated to be worth more than 300 billion US Dollars and to be increasing 20% per year.

Related Conferences

5th International ConferenceonCell and Gene Therapy May 19-21, 2016 San Antonio, USA; International Conference on Restorative Medicine October 24-26, 2016 Chicago, USA; InternationalConference on Molecular Biology October 13-15, 2016 Dubai, UAE; 2nd International Conference on Bio-banking August 18-19, 2016 Portland, USA; ISSCR Annual Meeting 22-25 June, 2016 San Francisco, California, USA; Keystone Cardiac Development, Regeneration and Repair (Z2) April 3 7, 2016 Snowbird, Utah, USA;EMBL Hematopoietic Stem Cells: From the Embryo to the Aging Organism, June 3-5, 2016 Heidelberg, Germany; ISSCR Pluripotency: From basic science to therapeutic applications March 22-24, 2016 Kyoto, Japan

Organ Engineering

This interdisciplinary engineering has attracted much attention as a new therapeutic means that may overcome the drawbacks involved in the current artificial organs and organtransplantationthat have been also aiming at replacing lost or severely damaged tissues or organs. Tissue engineering and regenerative medicine is an exciting research area that aims at regenerative alternatives to harvested tissues for organ transplantation with soft tissues. Although significant progress has been made in thetissue engineeringfield, many challenges remain and further development in this area will require ongoing interactions and collaborations among the scientists from multiple disciplines, and in partnership with the regulatory and the funding agencies. As a result of the medical and market potential, there is significant academic and corporate interest in this technology.

Related Conferences

International Conference on Restorative Medicine October 24-26, 2016 Chicago, USA; 5th InternationalConference on Cell and Gene Therapy May 19-21, 2016 San Antonio, USA; 5th International Conference on Regenerative Medicine September 12-14, 2016 Berlin, Germany; 2nd International Conference on Tissue preservation August 18-19, 2016 Portland, USA;Cell and Gene TherapyJanuary 25-27, 2016 Washington D.C., USA; ISSCR Stem Cell Models of Neural Degeneration and Disease February 1-3, 2016 Dresden, Germany; Craniofacial Morphogenesis and Tissue Regeneration March 12-18, 2016 California, USA; Keystone Stem Cells and Cancer (C1) March 6-10, Colorado, USA; Keystone Stem Cells and Regeneration in the Digestive Organs (X6) March 13 17 Colorado, USA

Cancer Stem Cells

The characterization of cancer stem cell is done by identifying the cell within a tumor that possesses the capacity to self-renew and to cause theheterogeneous lineagesof cancer cells that comprise the tumor. This stem cell which acts as precursor for the cancer acts as a tool against it indulging the reconstruction of cancer stem cells, implies as the therapeutic implications and challenging the gaps globally. The global stem cell market will grow from about $5.6 billion in 2013 to nearly $10.6 billion in 2018, registering a compound annual growth rate (CAGR) of 3.6% from 2013 through 2018. The Americas is the largest region of globalstem cellmarket, with a market share of about $2.0 billion in 2013. The region is projected to increase to nearly $3.9 billion by 2018, with a CAGR of 13.9% for the period of 2013 to 2018. Europe is the second largest segment of the global stem cell market and is expected to grow at a CAGR of 13.4% reaching about $2.4 billion by 2018 from nearly $1.4 billion in 2013.

Related Conferences

5th InternationalConference Cell and Gene Therapy May 19-21, 2016 San Antonio, USA; International Conference on Molecular Biology October 13-15, 2016 Dubai, UAE; 5th International Conference on Tissue EngineeringSeptember 12-14, 2016 Berlin, Germany; 2nd International Conference on Tissue preservationAugust 18-19, 2016 Portland, USA; Molecular and Cellular Basis of Growth and Regeneration (A3) January 10 14, 2016 Colorado, USA; Cell and Gene TherapyJanuary 25-27, 2016 Washington D.C., USA; ISSCR Stem Cell Models of Neural Degeneration and Disease March 13 17, 2016 Dresden, Germany; Craniofacial Morphogenesis and Tissue Regeneration March 12-18, 2016 California, USA; World Stem Cells Congress May 18-20, 2016 London, UK

Bone Tissue Engineering

Tissue engineering ofmusculoskeletal tissues, particularly bone and cartilage, is a rapidly advancing field. In bone, technology has centered on bone graft substitute materials and the development of biodegradable scaffolds. Recently, tissue engineering strategies have included cell and gene therapy. The availability of growth factors and the expanding knowledge base concerning the bone regeneration with modern techniques like recombinant signaling molecules, solid free form fabrication of scaffolds, synthetic cartilage, Electrochemical deposition,spinal fusionand ossification are new generated techniques for tissue-engineering applications. The worldwide market for bone and cartilage repairs strategies is estimated about $300 million. During the last 10/15 years, the scientific community witnessed and reported the appearance of several sources of stem cells with both osteo and chondrogenic potential.

Related Conferences

5th International Conference on Tissue Engineering and Regenerative Medicine September 12-14, 2016 Berlin, Germany; 3rd 2nd International Conference on Tissue preservation and Bio-banking August 18-19, 2016 Portland, USA; 5th International Conference on Cell and Gene Therapy May 19-21, 2016 San Antonio, USA; International Conference on Restorative Medicine October 24-26, 2016 Chicago, USA; 10th World Biomaterials Congress May 17-22, 2016 Quebec, Canada; 2016 TERMIS-EU Conference June 28- July1, 2016 Uppsala, Sweden; 2016 TERMIS-AP Conference Tamsui Town of New Taipei City May 23-28, 2016; 2016 TERMIS-AM Conference September 3-6, 2016, San Diego, USA; Pluripotency: From basic science to therapeutic applications 22-24 March 2016 Kyoto, Japan

Scaffolds

Scaffolds are one of the three most important elements constituting the basic concept of regenerative medicine, and are included in the core technology of regenerative medicine. Every day thousands of surgical procedures are performed to replace or repair tissue that has been damaged through disease or trauma. The developing field of tissue engineering (TE) aims to regeneratedamaged tissuesby combining cells from the body with highly porous scaffold biomaterials, which act as templates for tissue regeneration, to guide the growth of new tissue. Scaffolds has a prominent role in tissue regeneration the designs, fabrication, 3D models, surface ligands and molecular architecture, nanoparticle-cell interactions and porous of thescaffoldsare been used in the field in attempts to regenerate different tissues and organs in the body. The world stem cell market was approximately 2.715 billion dollars in 2010, and with a growth rate of 16.8% annually, a market of 6.877 billion dollars will be formed in 2016. From 2017, the expected annual growth rate is 10.6%, which would expand the market to 11.38 billion dollars by 2021.

Related Conferences

InternationalConference on Restorative MedicineOctober 24-26, 2016 Chicago, USA; 5th InternationalConference onCell and Gene TherapyMay 19-21, 2016 San Antonio, USA; 5th InternationalConference on Regenerative MedicineSeptember 12-14, 2016 Berlin, Germany; 2ndInternational Conference on Tissue preservationAugust 18-19, 2016 Portland, USA;Cell and Gene TherapyJanuary 25-27, 2016 Washington D.C., USA; ISSCRStem Cell Modelsof Neural Degeneration and Disease February 1-3, 2016 Dresden, Germany; Craniofacial Morphogenesis andTissue RegenerationMarch 12-18, 2016 California, USA; KeystoneStem Cells and Cancer(C1) March 6-10, Colorado, USA; KeystoneStem Cells and Regenerationin the Digestive Organs (X6) March 13 17 Colorado, USA

Tissue Regeneration Technologies

Guided tissue regeneration is defined as procedures attempting to regenerate lost periodontal structures through differential tissue responses. Guidedbone regenerationtypically refers to ridge augmentation or bone regenerative procedures it typically refers to regeneration of periodontal therapy. The recent advancements and innovations in biomedical and regenerative tissue engineering techniques include the novel approach of guided tissue regeneration and combination ofnanotechnologyand regenerative medicine.

Related Conferences

5th InternationalConferenceCell and Gene TherapyMay 19-21, 2016 San Antonio, USA; InternationalConference on Restorative MedicineOctober 24-26, 2016 Chicago, USA; InternationalConference on Molecular BiologyOctober 13-15, 2016 Dubai, UAE; 2nd InternationalConference on Bio-bankingAugust 18-19, 2016 Portland, USA;ISSCR Annual Meeting22-25 June, 2016 San Francisco, California, USA; KeystoneCardiac Development, Regeneration and Repair (Z2) April 3 7, 2016 Snowbird, Utah, USA;EMBLHematopoietic Stem Cells: From the Embryo to the Aging Organism, June 3-5, 2016 Heidelberg, Germany; ISSCRPluripotency: From basic science to therapeutic applications March 22-24, 2016 Kyoto, Japan

Regeneration and Therapeutics

Regenerative medicinecan be defined as a therapeutic intervention which replaces or regenerates human cells, tissues or organs, to restore or establish normal function and deploys small molecule drugs, biologics, medical devices and cell-based therapies. It deals with the different therapeutic uses like stem cells for tissue repair, tissue injury and healing process, cardiacstem cell therapyfor regeneration, functional regenerative recovery, effects of aging on tissuerepair/regeneration, corneal regeneration & degeneration. The global market is expected to reach $25.5 billion by 2011 and will further grow to $36.1 billion by 2016 at a CAGR of 7.2%. It is expected to reach $65 billion mark by 2024.

Related Conferences

5th InternationalConference on Tissue Engineering and Regenerative MedicineSeptember 12-14, 2016 Berlin, Germany; 5th InternationalConference onCell and Gene TherapyMay 19-21, 2016 San Antonio, USA; InternationalConference on Cancer Immunologyand ImmunotherapyJuly 28-30, 2016 Melbourne, Australia; InternationalConference on Molecular BiologyOctober 13-15, 2016 Dubai, UAE; Tissue Niches andResident Stem Cells in Adult EpitheliaGordon Research Conference,Regulation of Tissue Homeostasisby Signalling in the Stem Cell Niche August 7-12, Hong Kong, China;10 Years of IPSCs, Cell Symposia, September 25-27, 2016 Berkeley, CA, USA; WorldStem Cells and Regenerative Medicine CongressMay 18-20, 2016 London, UK; Notch Signaling in Development,Regenerationand Disease Gordon Research Conference, July 31-August 5, 2016 Lewiston, ME, USA

Regenerative medicine

Regenerative medicine is a branch oftranslational researchin tissue engineering and molecular biology which deals with the process of replacing, engineering or regenerating human cells, tissues or organs to restore or establish normal function. The latest developments involve advances in cell and gene therapy and stem cell research, molecular therapy, dental and craniofacial regeneration.Regenerative medicineshave the unique ability to repair, replace and regenerate tissues and organs, affected due to some injury, disease or due to natural aging process. These medicines are capable of restoring the functionality of cells and tissues. The global regenerative medicine market will reach $ 67.6 billion by 2020 from $16.4 billion in 2013, registering a CAGR of 23.2% during forecast period (2014 - 2020). Small molecules and biologics segment holds prominent market share in the overall regenerative medicine technology market and is anticipated to grow at a CAGR of 18.9% during the forecast period.

Related Conferences

InternationalConference on Restorative MedicineOctober 24-26, 2016 Chicago, USA; 5th InternationalConference onCell and Gene TherapyMay 19-21, 2016 San Antonio, USA; 5th InternationalConference on Regenerative MedicineSeptember 12-14, 2016 Berlin, Germany; 2ndInternational Conference on Tissue preservationAugust 18-19, 2016 Portland, USA;Cell and Gene TherapyJanuary 25-27, 2016 Washington D.C., USA; ISSCRStem Cell Modelsof Neural Degeneration and Disease February 1-3, 2016 Dresden, Germany; Craniofacial Morphogenesis andTissue RegenerationMarch 12-18, 2016 California, USA; KeystoneStem Cells and Cancer(C1) March 6-10, Colorado, USA; KeystoneStem Cells and Regenerationin the Digestive Organs (X6) March 13 17 Colorado, USA

Applications of Tissue Engineering

The applications of tissue engineering and regenerative medicine are innumerable as they mark the replacement of medication andorgan replacement. The applications involve cell tracking andtissue imaging, cell therapy and regenerative medicine, organ harvesting, transport and transplant, the application of nanotechnology in tissue engineering and regenerative medicine and bio banking. Globally the research statistics are increasing at a vast scale and many universities and companies are conducting events on the subject regenerative medicine conference like tissue implants workshops, endodontics meetings, tissue biomarkers events, tissue repair meetings, regenerative medicine conferences, tissue engineering conference, regenerative medicine workshop, veterinary regenerative medicine, regenerative medicine symposiums, tissue regeneration conferences, regenerative medicine congress.

Related Conferences

5th InternationalConferenceCell and Gene TherapyMay 19-21, 2016 San Antonio, USA; InternationalConference on Restorative MedicineOctober 24-26, 2016 Chicago, USA; InternationalConference on Molecular BiologyOctober 13-15, 2016 Dubai, UAE; 2nd InternationalConference on Bio-bankingAugust 18-19, 2016 Portland, USA;ISSCR Annual Meeting22-25 June, 2016 San Francisco, California, USA; KeystoneCardiac Development, Regeneration and Repair (Z2) April 3 7, 2016 Snowbird, Utah, USA;EMBLHematopoietic Stem Cells: From the Embryo to the Aging Organism, June 3-5, 2016 Heidelberg, Germany; ISSCRPluripotency: From basic science to therapeutic applications March 22-24, 2016 Kyoto, Japan

Regenerative Medicine Market

There are strong pricing pressures from public healthcare payers globally as Governments try to reduce budget deficits. Regenerative medicine could potentially save public health bodies money by reducing the need for long-term care and reducing associated disorders, with potential benefits for the world economy as a whole.The global market fortissue engineeringand regeneration products reached $55.9 billion in 2010, is expected to reach $59.8 billion by 2011, and will further grow to $89.7 billion by 2016 at a compounded annual growth rate (CAGR) of 8.4%. It grows to $135 billion to 2024. The contribution of the European region was 43.3% of the market in 2010, a value of $24.2 billion. Themarketis expected to reach $25.5 billion by 2011 and will further grow to $36.1 billion by 2016 at a CAGR of 7.2%. It grows to $65 billion to 2024.

Related Conferences

5th InternationalConference on Tissue Engineeringand Regenerative MedicineSeptember 12-14, 2016 Berlin, Germany; 3rd 2nd InternationalConference on Tissue preservationand Bio-bankingAugust 18-19, 2016 Portland, USA; 5th InternationalConference on Cell and Gene TherapyMay 19-21, 2016 San Antonio, USA; InternationalConference on Restorative MedicineOctober 24-26, 2016 Chicago, USA; 10thWorld Biomaterials CongressMay 17-22, 2016 Quebec, Canada; 2016TERMIS-EU ConferenceJune 28- July1, 2016 Uppsala, Sweden; 2016TERMIS-AP ConferenceTamsui Town of New Taipei City May 23-28, 2016; 2016TERMIS-AM ConferenceSeptember 3-6, 2016, San Diego, USA;Pluripotency: From basic science to therapeutic applications22-24 March 2016 Kyoto, Japan

Regenerative Medicine Europe

Leading EU nations with strong biotech sectors such as the UK and Germany are investing heavily in regenerative medicine, seeking competitive advantage in this emerging sector. The commercial regenerative medicine sector faces governance challenges that include a lack of proven business models, an immature science base and ethical controversy surrounding hESC research. The recent global downturn has exacerbated these difficulties: private finance has all but disappeared; leading companies are close to bankruptcy, and start-ups are struggling to raise funds. In the UK the government has responded by announcing 21.5M funding for the regenerative medicine industry and partners. But the present crisis extends considerably beyond regenerative medicine alone, affecting much of the European biotech sector. A 2009 European Commission (EC) report showed the extent to which the global recession has impacted on access to VC finance in Europe: 75% of biopharma companies in Europe need capital within the next two years if they are to continue their current range of activities.

Related Conferences

InternationalConference on Restorative MedicineOctober 24-26, 2016 Chicago, USA; 5th InternationalConference onCell and Gene TherapyMay 19-21, 2016 San Antonio, USA; 5th InternationalConference on Regenerative MedicineSeptember 12-14, 2016 Berlin, Germany; 2ndInternational Conference on Tissue preservationAugust 18-19, 2016 Portland, USA;Cell and Gene TherapyJanuary 25-27, 2016 Washington D.C., USA; ISSCRStem Cell Modelsof Neural Degeneration and Disease February 1-3, 2016 Dresden, Germany; Craniofacial Morphogenesis andTissue RegenerationMarch 12-18, 2016 California, USA; KeystoneStem Cells and Cancer(C1) March 6-10, Colorado, USA; KeystoneStem Cells and Regenerationin the Digestive Organs (X6) March 13 17 Colorado, USA

Embryonic Stem Cell

Embryonic stem cells are pluripotent, meaning they are able to grow (i.e. differentiate) into all derivatives of the three primary germ layers: ectoderm, endoderm and mesoderm. In other words, they can develop into each of the more than 200 cell types of the adult body as long as they are specified to do so. Embryonic stem cells are distinguished by two distinctive properties: their pluripotency, and their ability to replicate indefinitely. ES cells are pluripotent, that is, they are able to differentiate into all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm. These include each of the more than 220 cell types in the adult body. Pluripotency distinguishes embryonic stem cells from adult stem cells found in adults; while embryonic stem cells can generate all cell types in the body, adult stem cells are multipotent and can produce only a limited number of cell types. Additionally, under defined conditions, embryonic stem cells are capable of propagating themselves indefinitely. This allows embryonic stem cells to be employed as useful tools for both research and regenerative medicine, because they can produce limitless numbers of themselves for continued research or clinical use.

Related Conferences

5th InternationalConference on Tissue Engineering and Regenerative MedicineSeptember 12-14, 2016 Berlin, Germany; 5th InternationalConference onCell and Gene TherapyMay 19-21, 2016 San Antonio, USA; InternationalConference on Cancer Immunologyand ImmunotherapyJuly 28-30, 2016 Melbourne, Australia; InternationalConference on Molecular BiologyOctober 13-15, 2016 Dubai, UAE; Tissue Niches andResident Stem Cells in Adult EpitheliaGordon Research Conference,Regulation of Tissue Homeostasisby Signalling in the Stem Cell Niche August 7-12, Hong Kong, China;10 Years of IPSCs, Cell Symposia, September 25-27, 2016 Berkeley, CA, USA; WorldStem Cells and Regenerative Medicine CongressMay 18-20, 2016 London, UK; Notch Signaling in Development,Regenerationand Disease Gordon Research Conference, July 31-August 5, 2016 Lewiston, ME, USA

Stem Cell Transplant

Stem cell transplantation is a procedure that is most often recommended as a treatment option for people with leukemia, multiple myeloma, and some types of lymphoma. It may also be used to treat some genetic diseases that involve the blood. During a stem cell transplant diseased bone marrow (the spongy, fatty tissue found inside larger bones) is destroyed with chemotherapy and/or radiation therapy and then replaced with highly specialized stem cells that develop into healthy bone marrow. Although this procedure used to be referred to as a bone marrow transplant, today it is more commonly called a stem cell transplant because it is stem cells in the blood that are typically being transplanted, not the actual bone marrow tissue.

Related Conferences

5th InternationalConference Cell and Gene TherapyMay 19-21, 2016 San Antonio, USA; InternationalConference on Molecular BiologyOctober 13-15, 2016 Dubai, UAE; 5th InternationalConference on Tissue EngineeringSeptember 12-14, 2016 Berlin, Germany; 2nd InternationalConference on Tissue preservationAugust 18-19, 2016 Portland, USA; Molecular and Cellular Basis ofGrowth and Regeneration(A3) January 10 14, 2016 Colorado, USA;Cell and Gene TherapyJanuary 25-27, 2016 Washington D.C., USA; ISSCRStem Cell Modelsof Neural Degeneration and Disease March 13 17, 2016 Dresden, Germany; Craniofacial Morphogenesis andTissue RegenerationMarch 12-18, 2016 California, USA;World Stem Cells CongressMay 18-20, 2016 London, UK

Market Analysis Report:

Tissue engineering is an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ. Regenerative medicine is not one discipline. It can be defined as a therapeutic intervention which replaces or regenerates human cells, tissues or organs, to restore or establish normal function and deploys small molecule drugs, biologics, medical devices and cell-based therapies

Currently it has emerged as a rapidly diversifying field with the potential to address the worldwide organ shortage issue and comprises of tissue regeneration and organ replacement. Regenerative medicine could potentially save public health bodies money by reducing the need for long-term care and reducing associated disorders, with potential benefits for the world economy as a whole.The global tissue engineering and regeneration market reached $17 billion in 2013. This market is expected to grow to nearly $20.8 billion in 2014 and $56.9 billion in 2019, a compound annual growth rate (CAGR) of 22.3%. On the basis of geography, Europe holds the second place in the global market in the field of regenerative medicine & tissue engineering. In Europe countries like UK, France and Germany are possessing good market shares in the field of regenerative medicine and tissue engineering. Spain and Italy are the emerging market trends for tissue engineering in Europe.

Tissue engineering is "an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ. Currently it has emerged as a rapidly diversifying field with the potential to address the worldwide organ shortage issue and comprises of tissue regeneration and organ replacement. A novel set of tissue replacement parts and implementation strategies had shown a great revolution in this field. Cells placed on or within the tissue constructs is the most common methodology in tissue engineering.

Regenerative medicine is not one discipline. It can be defined as a therapeutic intervention which replaces or regenerates human cells, tissues or organs, to restore or establish normal function and deploys small molecule drugs, biologics, medical devices and cell-based therapies

This field continues to evolve. In addition to medical applications, non-therapeutic applications include using tissues as biosensors to detect biological or chemical threat agents, and tissue chips that can be used to test the toxicity of an experimental medication. Tissue Engineering and Regenerative Medicine is the major field in Medicine, which is still under research and the advancements are maximizing day to day.

Regenerative Medicine-2015 is an engrossed a vicinity of cognizant discussions on novel subjects like Tissue Regeneration, Materials & Designs for Tissue Engineering, Stem CellTools to Battle Cancer, Bioreactors in Tissue Engineering, Regeneration & Therapeutics, Cord Blood & Regenerative Medicine and Clinical Medicine, to mention a few. The three days event implants a firm relation of upcoming strategies in the field of Tissue Science & Regenerative Medicine with the scientific community. The conceptual and applicable knowledge shared, will also foster organizational collaborations to nurture scientific accelerations.We bring together business, creative, and technology leaders from the tissue engineering, marketing, and research industry for the most current and relevant.

Berlin is one of the largest and most diverse science regions in Europe. Roughly 200,000 people from around the world teach, research, work and study here. Approximately 17 percent of all students come from abroad, most of them from China, Russia and the USA. Many cooperative programs link Berlins institutes of higher education with partner institutes around the world. Berlin is a city of science at the heart of Europe a city whose history of scientific excellence stems from its many important research institutions and its long track record of scientific breakthroughs. Berlin has numerous modern Technology Centers. Their science-oriented infrastructure makes them attractive locations for young, technology-oriented companies.

Germany places great emphasis on globally networked research cooperation. Many organizations support international researchers and academics: Today more than 32,000 are being supported with scholarships. Besides this, research funding in Germany has the goal of financing the development of new ideas and technologies. The range covers everything from basic research in natural sciences, new technologies to structural research funding at institutions of higher education. On the basis of geography, the regenerative medicine bone and joint market Europe hold the second place in the global market in the field of regenerative medicine & tissue engineering. The market growth is expected to reach $65 billion by 2024 in Europe. In Europe countries like UK, France, and Germany are possessing good market share in the field of regenerative medicine and tissue engineering. Spain and Italy are the emerging market trends for tissue engineering in Europe. As per the scope and emerging market for tissue engineering and regenerative medicine Berlin has been selected as Venue for the 5th International Conference on Tissue Science and Regenerative Medicine.

Meet Your Target MarketWith members from around the world focused on learning about Advertising and marketing, this is the single best opportunity to reach the largest assemblage of participants from the tissue engineering and regenerative medicine community. The meeting engrossed a vicinity of cognizant discussions on novel subjects like Tissue Regeneration, Materials & Designs for Tissue Engineering, Stem CellTools to Battle Cancer, Bioreactors in Tissue Engineering, Regeneration & Therapeutics, Cord Blood & Regenerative Medicine and Clinical Medicine, to mention a few. The three days event implants a firm relation of upcoming strategies in the field of Tissue Engineering & Regenerative Medicine with the scientific community. The conceptual and applicable knowledge shared, will also foster organizational collaborations to nurture scientific accelerations.Conduct demonstrations, distribute information, meet with current and potential customers, make a splash with a new product line, and receive name recognition.

International Stem Cell Forum (ISCF)

International Society for Stem Cell Research (ISSCR)

UK Medical Research Council (MRC)

Australian Stem Cell Center

Canadian Institutes of Health Research (CIHR)

Euro Stem Cell (ACR)

Center for Stem Cell Biology

Stem Cell Research Singapore

UK National Stem Cell Network

Spain Mobile Marketing Association

European Marketing Confederation (EMC)

European Letterbox Marketing Association(ELMA)

European Sales & Marketing Association (ESMA)

The Incentive Marketing Association (IMA Europe)

European Marketing Academy

Figure 1: Statistical Analysis of Societies and Associations

Source: Reference7

Presidents or Vice Presidents/ Directors of Associations and Societies, CEOs of the companies associated with regenerative medicine and tissue engineering Consumer Products. Retailers, Marketing, Advertising and Promotion Agency Executives, Solution Providers (digital and mobile technology, P-O-P design, retail design, and retail execution), Professors and Students from Academia in the study of Marketing and Advertising filed.

Industry 40%

Academia 50%

Others 10%

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Regenerative Medicine Conferences | Tissue Engineering ...

Cardiac Stem Cells Comments Off on Regenerative Medicine Conferences | Tissue Engineering … | October 3rd, 2016

Unlike cell lines, primary cells are non-transformed, non-immortalized cells that are isolated directly from tissue. Closely mimicking a living model and yielding more biologically and physiologically relevant results, human primary cells have become an essential tool in the development of therapeutic treatments. Choose from an extensive range of fresh and cryopreserved peripheral blood products, as well as cryopreserved cord blood products, to incorporate into your research workflow.

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*Certain products are only available in select territories. Please contact your local Sales representative or the Product & Scientific Support team at techsupport@stemcell.com for further information. 1 Cultured cell product.

Human peripheral blood cells are isolated from adult whole blood or from a leukapheresis preparation produced using state-of-the-art apheresis systems. These apheresis collections, known as "Leuko Paks", contain very high concentrations of mononuclear cells and are available in the following Pak sizes: full, half and quarter Pak. Specific cell subsets are purified using STEMCELL's cell isolation products. Fresh whole blood products are collected directly into blood bags using acid-citrate-dextrose solution A (ACDA) or citrate-phosphate-dextrose (CPD) as the anticoagulant.

Human cord blood is collected using citrate-phosphate-dextrose (CPD) as the anticoagulant. Mononuclear cells are obtained by density gradient centrifugation. Specific cell subsets are obtained using STEMCELLs cell isolation products.

Human adult bone marrow cells are drawn from the posterior iliac crest (25 mL/site) from a maximum of four sites per donor. Heparin is used as the anticoagulant. Mononuclear cells (MNCs) are obtained by density gradient centrifugation, and specific cell types are purified using STEMCELLs cell isolation products.

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Cryopreserved Leuko Pak, Whole Blood and Bone Marrow Products

Donor Screening: Donors are screened for HIV (1 & 2), Hepatitis B, and Hepatitis C. Cryopreserved products are shipped with negative test results from donor screening that is done within 90 days of collection.

Fresh Leuko Pak, Whole Blood and Bone Marrow Products

Donor Screening: Donors are screened for HIV (1 & 2), Hepatitis B, and Hepatitis C. If the donor was screened within 90 days of donation the product will be shipped with negative test results from donor screening. If the donor was not screened within 90 days of collection, a test sample will be taken at the time of donation and the product will be shipped before the screening results are available. In the unlikely event that a test result is positive, the customer will be contacted as soon as possible (usually within 24-72 hours from the time of shipment).

Cryopreserved Cord Blood Products

Donor Screening: Cord blood is only collected from mothers that have tested negative for HIV (1 & 2) and Hepatitis B during their pregnancy. Hepatitis C is tested for at the time of collection. Cryopreserved products are shipped with negative test results from donor screening.

Fresh Cord Blood Products

Donor Screening: Cord blood is only collected from mothers that have tested negative for HIV (1 & 2) and Hepatitis B during their pregnancy. Hepatitis C is tested for at the time of collection. Fresh cord blood products are shipped with negative test results for HIV (1 & 2) and Hepatitis B donor screening. Hepatitis C test results are not available at the time of shipment. In the unlikely event that the Hepatitis C test result is positive, the customer will be contacted as soon as possible (usually within 24-72 hours from the time of shipment).

Shipment date of fresh Leuko Pak or whole blood orders is subject to change based on the ability of donors to meet procedural requirements during collection or on changes in donor availability. Collections will be rescheduled as soon as possible according to customer requirements.

STEMCELL does not test for infectious diseases other than those listed above and the testing that is done cannot completely guarantee that the donor was virus-free. Therefore THESE PRODUCTS SHOULD BE TREATED AS POTENTIALLY INFECTIOUS and only used following appropriate handling precautions such as those described in biological safety level 2. When handling these products do not use sharps such as needles and syringes.

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Primary Cells Overview - stemcell.com

Bone Marrow Stem Cells Comments Off on Primary Cells Overview – stemcell.com | September 29th, 2016

by Jos Domen*, Amy Wagers** and Irving L. Weissman***

Blood and the system that forms it, known as the hematopoietic system, consist of many cell types with specialized functions (see Figure 2.1). Red blood cells (erythrocytes) carry oxygen to the tissues. Platelets (derived from megakaryocytes) help prevent bleeding. Granulocytes (neutrophils, basophils and eosinophils) and macrophages (collectively known as myeloid cells) fight infections from bacteria, fungi, and other parasites such as nematodes (ubiquitous small worms). Some of these cells are also involved in tissue and bone remodeling and removal of dead cells. B-lymphocytes produce antibodies, while T-lymphocytes can directly kill or isolate by inflammation cells recognized as foreign to the body, including many virus-infected cells and cancer cells. Many blood cells are short-lived and need to be replenished continuously; the average human requires approximately one hundred billion new hematopoietic cells each day. The continued production of these cells depends directly on the presence of Hematopoietic Stem Cells (HSCs), the ultimate, and only, source of all these cells.

Figure 2.1. Hematopoietic and stromal cell differentiation.

2001 Terese Winslow (assisted by Lydia Kibiuk)

The search for stem cells began in the aftermath of the bombings in Hiroshima and Nagasaki in 1945. Those who died over a prolonged period from lower doses of radiation had compromised hematopoietic systems that could not regenerate either sufficient white blood cells to protect against otherwise nonpathogenic infections or enough platelets to clot their blood. Higher doses of radiation also killed the stem cells of the intestinal tract, resulting in more rapid death. Later, it was demonstrated that mice that were given doses of whole body X-irradiation developed the same radiation syndromes; at the minimal lethal dose, the mice died from hematopoietic failure approximately two weeks after radiation exposure.1 Significantly, however, shielding a single bone or the spleen from radiation prevented this irradiation syndrome. Soon thereafter, using inbred strains of mice, scientists showed that whole-body-irradiated mice could be rescued from otherwise fatal hematopoietic failure by injection of suspensions of cells from blood-forming organs such as the bone marrow.2 In 1956, three laboratories demonstrated that the injected bone marrow cells directly regenerated the blood-forming system, rather than releasing factors that caused the recipients' cells to repair irradiation damage.35 To date, the only known treatment for hematopoietic failure following whole body irradiation is transplantation of bone marrow cells or HSCs to regenerate the blood-forming system in the host organisms.6,7

The hematopoietic system is not only destroyed by the lowest doses of lethal X-irradiation (it is the most sensitive of the affected vital organs), but also by chemotherapeutic agents that kill dividing cells. By the 1960s, physicians who sought to treat cancer that had spread (metastasized) beyond the primary cancer site attempted to take advantage of the fact that a large fraction of cancer cells are undergoing cell division at any given point in time. They began using agents (e.g., chemical and X-irradiation) that kill dividing cells to attempt to kill the cancer cells. This required the development of a quantitative assessment of damage to the cancer cells compared that inflicted on normal cells. Till and McCulloch began to assess quantitatively the radiation sensitivity of one normal cell type, the bone marrow cells used in transplantation, as it exists in the body. They found that, at sub-radioprotective doses of bone marrow cells, mice that died 1015 days after irradiation developed colonies of myeloid and erythroid cells (see Figure 2.1 for an example) in their spleens. These colonies correlated directly in number with the number of bone marrow cells originally injected (approximately 1 colony per 7,000 bone marrow cells injected).8 To test whether these colonies of blood cells derived from single precursor cells, they pre-irradiated the bone marrow donors with low doses of irradiation that would induce unique chromosome breaks in most hematopoietic cells but allow some cells to survive. Surviving cells displayed radiation-induced and repaired chromosomal breaks that marked each clonogenic (colony-initiating) hematopoietic cell.9 The researchers discovered that all dividing cells within a single spleen colony, which contained different types of blood cells, contained the same unique chromosomal marker. Each colony displayed its own unique chromosomal marker, seen in its dividing cells.9 Furthermore, when cells from a single spleen colony were re-injected into a second set of lethally-irradiated mice, donor-derived spleen colonies that contained the same unique chromosomal marker were often observed, indicating that these colonies had been regenerated from the same, single cell that had generated the first colony. Rarely, these colonies contained sufficient numbers of regenerative cells both to radioprotect secondary recipients (e.g., to prevent their deaths from radiation-induced blood cell loss) and to give rise to lymphocytes and myeloerythroid cells that bore markers of the donor-injected cells.10,11 These genetic marking experiments established the fact that cells that can both self-renew and generate most (if not all) of the cell populations in the blood must exist in bone marrow. At the time, such cells were called pluripotent HSCs, a term later modified to multipotent HSCs.12,13 However, identifying stem cells in retrospect by analysis of randomly chromosome-marked cells is not the same as being able to isolate pure populations of HSCs for study or clinical use.

Achieving this goal requires markers that uniquely define HSCs. Interestingly, the development of these markers, discussed below, has revealed that most of the early spleen colonies visible 8 to 10 days after injection, as well as many of the later colonies, visible at least 12 days after injection, are actually derived from progenitors rather than from HSCs. Spleen colonies formed by HSCs are relatively rare and tend to be present among the later colonies.14,15 However, these findings do not detract from Till and McCulloch's seminal experiments to identify HSCs and define these unique cells by their capacities for self-renewal and multilineage differentiation.

While much of the original work was, and continues to be, performed in murine model systems, strides have been made to develop assays to study human HSCs. The development of Fluorescence Activated Cell Sorting (FACS) has been crucial for this field (see Figure 2.2). This technique enables the recognition and quantification of small numbers of cells in large mixed populations. More importantly, FACS-based cell sorting allows these rare cells (1 in 2000 to less than 1 in 10,000) to be purified, resulting in preparations of near 100% purity. This capability enables the testing of these cells in various assays.

Figure 2.2. Enrichment and purification methods for hematopoietic stem cells. Upper panels illustrate column-based magnetic enrichment. In this method, the cells of interest are labeled with very small iron particles (A). These particles are bound to antibodies that only recognize specific cells. The cell suspension is then passed over a column through a strong magnetic field which retains the cells with the iron particles (B). Other cells flow through and are collected as the depleted negative fraction. The magnet is removed, and the retained cells are collected in a separate tube as the positive or enriched fraction (C). Magnetic enrichment devices exist both as small research instruments and large closed-system clinical instruments.

Lower panels illustrate Fluorescence Activated Cell Sorting (FACS). In this setting, the cell mixture is labeled with fluorescent markers that emit light of different colors after being activated by light from a laser. Each of these fluorescent markers is attached to a different monoclonal antibody that recognizes specific sets of cells (D). The cells are then passed one by one in a very tight stream through a laser beam (blue in the figure) in front of detectors (E) that determine which colors fluoresce in response to the laser. The results can be displayed in a FACS-plot (F). FACS-plots (see figures 3 and 4 for examples) typically show fluorescence levels per cell as dots or probability fields. In the example, four groups can be distinguished: Unstained, red-only, green-only, and red-green double labeling. Each of these groups, e.g., green fluorescence-only, can be sorted to very high purity. The actual sorting happens by breaking the stream shown in (E) into tiny droplets, each containing 1 cell, that then can be sorted using electric charges to move the drops. Modern FACS machines use three different lasers (that can activate different set of fluorochromes), to distinguish up to 8 to 12 different fluorescence colors and sort 4 separate populations, all simultaneously.

Magnetic enrichment can process very large samples (billions of cells) in one run, but the resulting cell preparation is enriched for only one parameter (e.g., CD34) and is not pure. Significant levels of contaminants (such as T-cells or tumor cells) remain present. FACS results in very pure cell populations that can be selected for several parameters simultaneously (e.g., Linneg, CD34pos, CD90pos), but it is more time consuming (10,000 to 50,000 cells can be sorted per second) and requires expensive instrumentation.

2001 Terese Winslow (assisted by Lydia Kibiuk)

Assays have been developed to characterize hematopoietic stem and progenitor cells in vitro and in vivo (Figure 2.3).16,17In vivo assays that are used to study HSCs include Till and McCulloch's classical spleen colony forming (CFU-S) assay,8 which measures the ability of HSC (as well as blood-forming progenitor cells) to form large colonies in the spleens of lethally irradiated mice. Its main advantage (and limitation) is the short-term nature of the assay (now typically 12 days). However, the assays that truly define HSCs are reconstitution assays.16,18 Mice that have been quot;preconditionedquot; by lethal irradiation to accept new HSCs are injected with purified HSCs or mixed populations containing HSCs, which will repopulate the hematopoietic systems of the host mice for the life of the animal. These assays typically use different types of markers to distinguish host and donor-derived cells.

For example, allelic assays distinguish different versions of a particular gene, either by direct analysis of dna or of the proteins expressed by these alleles. These proteins may be cell-surface proteins that are recognized by specific monoclonal antibodies that can distinguish between the variants (e.g., CD45 in Figure 2.3) or cellular proteins that may be recognized through methods such as gel-based analysis. Other assays take advantage of the fact that male cells can be detected in a female host by detecting the male-cell-specific Y-chromosome by molecular assays (e.g., polymerase chain reaction, or PCR).

Figure 2.3. Assays used to detect hematopoietic stem cells. The tissue culture assays, which are used frequently to test human cells, include the ability of the cells to be tested to grow as quot;cobblestonesquot; (the dark cells in the picture) for 5 to 7 weeks in culture. The Long Term Culture-Initiating Cell assay measures whether hematopoietic progenitor cells (capable of forming colonies in secondary assays, as shown in the picture) are still present after 5 to 7 weeks of culture.

In vivo assays in mice include the CFU-S assay, the original stem cell assay discussed in the introduction. The most stringent hematopoietic stem cell assay involves looking for the long-term presence of donor-derived cells in a reconstituted host. The example shows host-donor recognition by antibodies that recognize two different mouse alleles of CD45, a marker present on nearly all blood cells. CD45 is also a good marker for distinguishing human blood cells from mouse blood cells when testing human cells in immunocompromised mice such as NOD/SCID. Other methods such as pcr-markers, chromosomal markers, and enzyme markers can also be used to distinguish host and donor cells.

Small numbers of HSCs (as few as one cell in mouse experiments) can be assayed using competitive reconstitutions, in which a small amount of host-type bone marrow cells (enough to radioprotect the host and thus ensure survival) is mixed in with the donor-HSC population. To establish long-term reconstitutions in mouse models, the mice are followed for at least 4 months after receiving the HSCs. Serial reconstitution, in which the bone marrow from a previously-irradiated and reconstituted mouse becomes the HSC source for a second irradiated mouse, extends the potential of this assay to test lifespan and expansion limits of HSCs. Unfortunately, the serial transfer assay measures both the lifespan and the transplantability of the stem cells. The transplantability may be altered under various conditions, so this assay is not the sine qua non of HSC function. Testing the in vivo activity of human cells is obviously more problematic.

Several experimental models have been developed that allow the testing of human cells in mice. These assays employ immunologically-incompetent mice (mutant mice that cannot mount an immune response against foreign cells) such as SCID1921 or NOD-SCID mice.22,23 Reconstitution can be performed in either the presence or absence of human fetal bone or thymus implants to provide a more natural environment in which the human cells can grow in the mice. Recently NOD/SCID/c-/- mice have been used as improved recipients for human HSCs, capable of complete reconstitution with human lymphocytes, even in the absence of additional human tissues.24 Even more promising has been the use of newborn mice with an impaired immune system (Rag-2-/-C-/-), which results in reproducible production of human B- and T-lymphoid and myeloerythroid cells.25 These assays are clearly more stringent, and thus more informative, but also more difficult than the in vitro HSC assays discussed below. However, they can only assay a fraction of the lifespan under which the cells would usually have to function. Information on the long-term functioning of cells can only be derived from clinical HSC transplantations.

A number of assays have been developed to recognize HSCs in vitro (e.g., in tissue culture). These are especially important when assaying human cells. Since transplantation assays for human cells are limited, cell culture assays often represent the only viable option. In vitro assays for HSCs include Long-Term Culture-Initializing Cell (LTC-IC) assays2628 and Cobble-stone Area Forming Cell (CAFC) assays.29 LTC-IC assays are based on the ability of HSCs, but not more mature progenitor cells, to maintain progenitor cells with clonogenic potential over at least a five-week culture period. CAFC assays measure the ability of HSCs to maintain a specific and easily recognizable way of growing under stromal cells for five to seven weeks after the initial plating. Progenitor cells can only grow in culture in this manner for shorter periods of time.

While initial experiments studied HSC activity in mixed populations, much progress has been made in specifically describing the cells that have HSC activity. A variety of markers have been discovered to help recognize and isolate HSCs. Initial marker efforts focused on cell size, density, and recognition by lectins (carbohydrate-binding proteins derived largely from plants),30 but more recent efforts have focused mainly on cell surface protein markers, as defined by monoclonal antibodies. For mouse HSCs, these markers include panels of 8 to 14 different monoclonal antibodies that recognize cell surface proteins present on differentiated hematopoietic lineages, such as the red blood cell and macrophage lineages (thus, these markers are collectively referred to as quot;Linquot;),13,31 as well as the proteins Sca-1,13,31 CD27,32 CD34,33 CD38,34 CD43,35 CD90.1(Thy-1.1),13,31 CD117(c-Kit),36 AA4.1,37 and MHC class I,30 and CD150.38 Human HSCs have been defined with respect to staining for Lin,39 CD34,40 CD38,41 CD43,35 CD45RO,42 CD45RA,42 CD59,43 CD90,39 CD109,44 CD117,45 CD133,46,47CD166,48 and HLA DR(human).49,50 In addition, metabolic markers/dyes such as rhodamine123 (which stains mitochondria),51 Hoechst33342 (which identifies MDR-type drug efflux activity),52 Pyronin-Y (which stains RNA),53 and BAAA (indicative of aldehyde dehydrogenase enzyme activity)54 have been described. While none of these markers recognizes functional stem cell activity, combinations (typically with 3 to 5 different markers, see examples below) allow for the purification of near-homogenous populations of HSCs. The ability to obtain pure preparations of HSCs, albeit in limited numbers, has greatly facilitated the functional and biochemical characterization of these important cells. However, to date there has been limited impact of these discoveries on clinical practice, as highly purified HSCs have only rarely been used to treat patients (discussed below). The undeniable advantages of using purified cells (e.g., the absence of contaminating tumor cells in autologous transplantations) have been offset by practical difficulties and increased purification costs.

Figure 2.4. Examples of Hematopoietic Stem Cell staining patterns in mouse bone marrow (top) and human mobilized peripheral blood (bottom). The plots on the right show only the cells present in the left blue box. The cells in the right blue box represent HSCs. Stem cells form a rare fraction of the cells present in both cases.

HSC assays, when combined with the ability to purify HSCs, have provided increasingly detailed insight into the cells and the early steps involved in the differentiation process. Several marker combinations have been developed that describe murine HSCs, including [CD117high, CD90.1low, Linneg/low, Sca-1pos],15 [CD90.1low, Linneg, Sca-1pos Rhodamine123low],55 [CD34neg/low, CD117pos, Sca-1pos, Linneg],33 [CD150 pos, CD48neg, CD244neg],38 and quot;side-populationquot; cells using Hoechst-dye.52 Each of these combinations allows purification of HSCs to near-homogeneity. Figure 2.4 shows an example of an antibody combination that can recognize mouse HSCs. Similar strategies have been developed to purify human HSCs, employing markers such as CD34, CD38, Lin, CD90, CD133 and fluorescent substrates for the enzyme, aldehyde dehydrogenase. The use of highly purified human HSCs has been mainly experimental, and clinical use typically employs enrichment for one marker, usually CD34. CD34 enrichment yields a population of cells enriched for HSC and blood progenitor cells but still contains many other cell types. However, limited trials in which highly FACS-purified CD34pos CD90pos HSCs (see Figure 2.4) were used as a source of reconstituting cells have demonstrated that rapid reconstitution of the blood system can reliably be obtained using only HSCs.5658

The purification strategies described above recognize a rare subset of cells. Exact numbers depend on the assay used as well as on the genetic background studied.16 In mouse bone marrow, 1 in 10,000 cells is a hematopoietic stem cell with the ability to support long-term hematopoiesis following transplantation into a suitable host. When short-term stem cells, which have a limited self-renewal capacity, are included in the estimation, the frequency of stem cells in bone marrow increases to 1 in 1,000 to 1 in 2,000 cells in humans and mice. The numbers present in normal blood are at least ten-fold lower than in marrow.

None of the HSC markers currently used is directly linked to an essential HSC function, and consequently, even within a species, markers can differ depending on genetic alleles,59 mouse strains,60 developmental stages,61 and cell activation stages.62,63 Despite this, there is a clear correlation in HSC markers between divergent species such as humans and mice. However, unless the ongoing attempts at defining the complete HSC gene expression patterns will yield usable markers that are linked to essential functions for maintaining the quot;stemnessquot; of the cells,64,65 functional assays will remain necessary to identify HSCs unequivocally.16

More recently, efforts at defining hematopoietic populations by cell surface or other FACS-based markers have been extended to several of the progenitor populations that are derived from HSCs (see Figure 2.5). Progenitors differ from stem cells in that they have a reduced differentiation capacity (they can generate only a subset of the possible lineages) but even more importantly, progenitors lack the ability to self-renew. Thus, they have to be constantly regenerated from the HSC population. However, progenitors do have extensive proliferative potential and can typically generate large numbers of mature cells. Among the progenitors defined in mice and humans are the Common Lymphoid Progenitor (CLP),66,67 which in adults has the potential to generate all of the lymphoid but not myeloerythroid cells, and a Common Myeloid Progenitor (CMP), which has the potential to generate all of the mature myeloerythroid, but not lymphoid, cells.68,69 While beyond the scope of this overview, hematopoietic progenitors have clinical potential and will likely see clinical use.70,71

Figure 2.5. Relationship between several of the characterized hematopoietic stem cells and early progenitor cells. Differentiation is indicated by colors; the more intense the color, the more mature the cells. Surface marker distinctions are subtle between these early cell populations, yet they have clearly distinct potentials. Stem cells can choose between self-renewal and differentiation. Progenitors can expand temporarily but always continue to differentiate (other than in certain leukemias). The mature lymphoid (T-cells, B-cells, and Natural Killer cells) and myeloerythroid cells (granulocytes, macrophages, red blood cells, and platelets) that are produced by these stem and progenitor cells are shown in more detail in Figure 2.1.

HSCs have a number of unique properties, the combination of which defines them as such.16 Among the core properties are the ability to choose between self-renewal (remain a stem cell after cell division) or differentiation (start the path towards becoming a mature hematopoietic cell). In addition, HSCs migrate in regulated fashion and are subject to regulation by apoptosis (programmed cell death). The balance between these activities determines the number of stem cells that are present in the body.

One essential feature of HSCs is the ability to self-renew, that is, to make copies with the same or very similar potential. This is an essential property because more differentiated cells, such as hematopoietic progenitors, cannot do this, even though most progenitors can expand significantly during a limited period of time after being generated. However, for continued production of the many (and often short-lived) mature blood cells, the continued presence of stem cells is essential. While it has not been established that adult HSCs can self-renew indefinitely (this would be difficult to prove experimentally), it is clear from serial transplantation experiments that they can produce enough cells to last several (at least four to five) lifetimes in mice. It is still unclear which key signals allow self-renewal. One link that has been noted is telomerase, the enzyme necessary for maintaining telomeres, the DNA regions at the end of chromosomes that protect them from accumulating damage due to DNA replication. Expression of telomerase is associated with self-renewal activity.72 However, while absence of telomerase reduces the self-renewal capacity of mouse HSCs, forced expression is not sufficient to enable HSCs to be transplanted indefinitely; other barriers must exist.73,74

It has proven surprisingly difficult to grow HSCs in culture despite their ability to self-renew. Expansion in culture is routine with many other cells, including neural stem cells and ES cells. The lack of this capacity for HSCs severely limits their application, because the number of HSCs that can be isolated from mobilized blood, umbilical cord blood, or bone marrow restricts the full application of HSC transplantation in man (whether in the treatment of nuclear radiation exposure or transplantation in the treatment of blood cell cancers or genetic diseases of the blood or blood-forming system). Engraftment periods of 50 days or more were standard when limited numbers of bone marrow or umbilical cord blood cells were used in a transplant setting, reflecting the low level of HSCs found in these native tissues. Attempts to expand HSCs in tissue culture with known stem-cell stimulators, such as the cytokines stem cell factor/steel factor (KitL), thrombopoietin (TPO), interleukins 1, 3, 6, 11, plus or minus the myeloerythroid cytokines GM-CSF, G-CSF, M-CSF, and erythropoietin have never resulted in a significant expansion of HSCs.16,75 Rather, these compounds induce many HSCs into cell divisions that are always accompanied by cellular differentiation.76 Yet many experiments demonstrate that the transplantation of a single or a few HSCs into an animal results in a 100,000-fold or greater expansion in the number of HSCs at the steady state while simultaneously generating daughter cells that permitted the regeneration of the full blood-forming system.7780 Thus, we do not know the factors necessary to regenerate HSCs by self-renewing cell divisions. By investigating genes transcribed in purified mouse LT-HSCs, investigators have found that these cells contain expressed elements of the Wnt/fzd/beta-catenin signaling pathway, which enables mouse HSCs to undergo self-renewing cell divisions.81,82 Overexpression of several other proteins, including HoxB48386 and HoxA987 has also been reported to achieve this. Other signaling pathways that are under investigation include Notch and Sonic hedgehog.75 Among the intracellular proteins thought to be essential for maintaining the quot;stem cellquot; state are Polycomb group genes, including Bmi-1.88 Other genes, such as c-Myc and JunB have also been shown to play a role in this process.89,90Much remains to be discovered, including the identity of the stimuli that govern self-renewal in vivo, as well as the composition of the environment (the stem cell quot;nichequot;) that provides these stimuli.91 The recent identification of osteoblasts, a cell type known to be involved in bone formation, as a critical component of this environment92,93 will help to focus this search. For instance, signaling by Angiopoietin-1 on osteoblasts to Tie-2 receptors on HSCs has recently been suggested to regulate stem cell quiescence (the lack of cell division).94 It is critical to discover which pathways operate in the expansion of human HSCs to take advantage of these pathways to improve hematopoietic transplantation.

Differentiation into progenitors and mature cells that fulfill the functions performed by the hematopoietic system is not a unique HSC property, but, together with the option to self-renew, defines the core function of HSCs. Differentiation is driven and guided by an intricate network of growth factors and cytokines. As discussed earlier, differentiation, rather than self-renewal, seems to be the default outcome for HSCs when stimulated by many of the factors to which they have been shown to respond. It appears that, once they commit to differentiation, HSCs cannot revert to a self-renewing state. Thus, specific signals, provided by specific factors, seem to be needed to maintain HSCs. This strict regulation may reflect the proliferative potential present in HSCs, deregulation of which could easily result in malignant diseases such as leukemia or lymphoma.

Migration of HSCs occurs at specific times during development (i.e., seeding of fetal liver, spleen and eventually, bone marrow) and under certain conditions (e.g., cytokine-induced mobilization) later in life. The latter has proven clinically useful as a strategy to enhance normal HSC proliferation and migration, and the optimal mobilization regimen for HSCs currently used in the clinic is to treat the stem cell donor with a drug such as cytoxan, which kills most of his or her dividing cells. Normally, only about 8% of LT-HSCs enter the cell cycle per day,95,96 so HSCs are not significantly affected by a short treatment with cytoxan. However, most of the downstream blood progenitors are actively dividing,66,68 and their numbers are therefore greatly depleted by this dose, creating a demand for a regenerated blood-forming system. Empirically, cytokines or growth factors such as G-CSF and KitL can increase the number of HSCs in the blood, especially if administered for several days following a cytoxan pulse. The optimized protocol of cytoxan plus G-CSF results in several self-renewing cell divisions for each resident LT-HSC in mouse bone marrow, expanding the number of HSCs 12- to 15-fold within two to three days.97 Then, up to one-half of the daughter cells of self-renewing dividing LT-HSCs (estimated to be up to 105 per mouse per day98) leave the bone marrow, enter the blood, and within minutes engraft other hematopoietic sites, including bone marrow, spleen, and liver.98 These migrating cells can and do enter empty hematopoietic niches elsewhere in the bone marrow and provide sustained hematopoietic stem cell self-renewal and hematopoiesis.98,99 It is assumed that this property of mobilization of HSCs is highly conserved in evolution (it has been shown in mouse, dog and humans) and presumably results from contact with natural cell-killing agents in the environment, after which regeneration of hematopoiesis requires restoring empty HSC niches. This means that functional, transplantable HSCs course through every tissue of the body in large numbers every day in normal individuals.

Apoptosis, or programmed cell death, is a mechanism that results in cells actively self-destructing without causing inflammation. Apoptosis is an essential feature in multicellular organisms, necessary during development and normal maintenance of tissues. Apoptosis can be triggered by specific signals, by cells failing to receive the required signals to avoid apoptosis, and by exposure to infectious agents such as viruses. HSCs are not exempt; apoptosis is one mechanism to regulate their numbers. This was demonstrated in transgenic mouse experiments in which HSC numbers doubled when the apoptosis threshold was increased.76 This study also showed that HSCs are particularly sensitive and require two signals to avoid undergoing apoptosis.

The best-known location for HSCs is bone marrow, and bone marrow transplantation has become synonymous with hematopoietic cell transplantation, even though bone marrow itself is increasingly infrequently used as a source due to an invasive harvesting procedure that requires general anesthesia. In adults, under steady-state conditions, the majority of HSCs reside in bone marrow. However, cytokine mobilization can result in the release of large numbers of HSCs into the blood. As a clinical source of HSCs, mobilized peripheral blood (MPB) is now replacing bone marrow, as harvesting peripheral blood is easier for the donors than harvesting bone marrow. As with bone marrow, mobilized peripheral blood contains a mixture of hematopoietic stem and progenitor cells. MPB is normally passed through a device that enriches cells that express CD34, a marker on both stem and progenitor cells. Consequently, the resulting cell preparation that is infused back into patients is not a pure HSC preparation, but a mixture of HSCs, hematopoietic progenitors (the major component), and various contaminants, including T cells and, in the case of autologous grafts from cancer patients, quite possibly tumor cells. It is important to distinguish these kinds of grafts, which are the grafts routinely given, from highly purified HSC preparations, which essentially lack other cell types.

In the late 1980s, umbilical cord blood (UCB) was recognized as an important clinical source of HSCs.100,101 Blood from the placenta and umbilical cord is a rich source of hematopoietic stem cells, and these cells are typically discarded with the afterbirth. Increasingly, UCB is harvested, frozen, and stored in cord blood banks, as an individual resource (donor-specific source) or as a general resource, directly available when needed. Cord blood has been used successfully to transplant children and (far less frequently) adults. Specific limitations of UCB include the limited number of cells that can be harvested and the delayed immune reconstitution observed following UCB transplant, which leaves patients vulnerable to infections for a longer period of time. Advantages of cord blood include its availability, ease of harvest, and the reduced risk of graft-versus-host-disease (GVHD). In addition, cord blood HSCs have been noted to have a greater proliferative capacity than adult HSCs. Several approaches have been tested to overcome the cell dose issue, including, with some success, pooling of cord blood samples.101,102 Ex vivo expansion in tissue culture, to which cord blood cells are more amenable than adult cells, is another approach under active investigation.103

The use of cord blood has opened a controversial treatment strategyembryo selection to create a related UCB donor.104 In this procedure, embryos are conceived by in vitro fertilization. The embryos are tested by pre-implantation genetic diagnosis, and embryos with transplantation antigens matching those of the affected sibling are implanted. Cord blood from the resulting newborn is then used to treat this sibling. This approach, successfully pioneered at the University of Minnesota, can in principle be applied to a wide variety of hematopoietic disorders. However, the ethical questions involved argue for clear regulatory guidelines.105

Embryonic stem (ES) cells form a potential future source of HSCs. Both mouse and human ES cells have yielded hematopoietic cells in tissue culture, and they do so relatively readily.106 However, recognizing the actual HSCs in these cultures has proven problematic, which may reflect the variability in HSC markers or the altered reconstitution behavior of these HSCs, which are expected to mimic fetal HSC. This, combined with the potential risks of including undifferentiated cells in an ES-cell-derived graft means that, based on the current science, clinical use of ES cell-derived HSCs remains only a theoretical possibility for now.

An ongoing set of investigations has led to claims that HSCs, as well as other stem cells, have the capacity to differentiate into a much wider range of tissues than previously thought possible. It has been claimed that, following reconstitution, bone marrow cells can differentiate not only into blood cells but also muscle cells (both skeletal myocytes and cardiomyocytes),107111 brain cells,112,113 liver cells,114,115 skin cells, lung cells, kidney cells, intestinal cells,116 and pancreatic cells.117 Bone marrow is a complex mixture that contains numerous cell types. In addition to HSCs, at least one other type of stem cell, the mesenchymal stem cell (MSC), is present in bone marrow. MSCs, which have become the subject of increasingly intense investigation, seem to retain a wide range of differentiation capabilities in vitro that is not restricted to mesodermal tissues, but includes tissues normally derived from other embryonic germ layers (e.g., neurons).118120MSCs are discussed in detail in Dr. Catherine Verfaillie's testimony to the President's Council on Bioethics at this website: refer to Appendix J (page 295) and will not be discussed further here. However, similar claims of differentiation into multiple diverse cell types, including muscle,111 liver,114 and different types of epithelium116 have been made in experiments that assayed partially- or fully-purified HSCs. These experiments have spawned the idea that HSCs may not be entirely or irreversibly committed to forming the blood, but under the proper circumstances, HSCs may also function in the regeneration or repair of non-blood tissues. This concept has in turn given rise to the hypothesis that the fate of stem cells is quot;plastic,quot; or changeable, allowing these cells to adopt alternate fates if needed in response to tissue-derived regenerative signals (a phenomenon sometimes referred to as quot;transdifferentiationquot;). This in turn seems to bolster the argument that the full clinical potential of stem cells can be realized by studying only adult stem cells, foregoing research into defining the conditions necessary for the clinical use of the extensive differentiation potential of embryonic stem cells. However, as discussed below, such quot;transdifferentiationquot; claims for specialized adult stem cells are controversial, and alternative explanations for these observations remain possible, and, in several cases, have been documented directly.

While a full discussion of this issue is beyond the scope of this overview, several investigators have formulated criteria that must be fulfilled to demonstrate stem cell plasticity.121,122 These include (i) clonal analysis, which requires the transfer and analysis of single, highly-purified cells or individually marked cells and the subsequent demonstration of both quot;normalquot; and quot;plasticquot; differentiation outcomes, (ii) robust levels of quot;plasticquot; differentiation outcome, as extremely rare events are difficult to analyze and may be induced by artefact, and (iii) demonstration of tissue-specific function of the quot;transdifferentiatedquot; cell type. Few of the current reports fulfill these criteria, and careful analysis of individually transplanted KTLS HSCs has failed to show significant levels of non-hematopoietic engraftment.123,124In addition, several reported trans-differentiation events that employed highly purified HSCs, and in some cases a very strong selection pressure for trans-differentiation, now have been shown to result from fusion of a blood cell with a non-blood cell, rather than from a change in fate of blood stem cells.125127 Finally, in the vast majority of cases, reported contributions of adult stem cells to cell types outside their tissue of origin are exceedingly rare, far too rare to be considered therapeutically useful. These findings have raised significant doubts about the biological importance and immediate clinical utility of adult hematopoietic stem cell plasticity. Instead, these results suggest that normal tissue regeneration relies predominantly on the function of cell type-specific stem or progenitor cells, and that the identification, isolation, and characterization of these cells may be more useful in designing novel approaches to regenerative medicine. Nonetheless, it is possible that a rigorous and concerted effort to identify, purify, and potentially expand the appropriate cell populations responsible for apparent quot;plasticityquot; events, characterize the tissue-specific and injury-related signals that recruit, stimulate, or regulate plasticity, and determine the mechanism(s) underlying cell fusion or transdifferentiation, may eventually enhance tissue regeneration via this mechanism to clinically useful levels.

Recent progress in genomic sequencing and genome-wide expression analysis at the RNA and protein levels has greatly increased our ability to study cells such as HSCs as quot;systems,quot; that is, as combinations of defined components with defined interactions. This goal has yet to be realized fully, as computational biology and system-wide protein biochemistry and proteomics still must catch up with the wealth of data currently generated at the genomic and transcriptional levels. Recent landmark events have included the sequencing of the human and mouse genomes and the development of techniques such as array-based analysis. Several research groups have combined cDNA cloning and sequencing with array-based analysis to begin to define the full transcriptional profile of HSCs from different species and developmental stages and compare these to other stem cells.64,65,128131 Many of the data are available in online databases, such as the NIH/NIDDK Stem Cell Genome Anatomy Projects. While transcriptional profiling is clearly a work in progress, comparisons among various types of stem cells may eventually identify sets of genes that are involved in defining the general quot;stemnessquot; of a cell, as well as sets of genes that define their exit from the stem cell pool (e.g., the beginning of their path toward becoming mature differentiated cells, also referred to as commitment). In addition, these datasets will reveal sets of genes that are associated with specific stem cell populations, such as HSCs and MSCs, and thus define their unique properties. Assembly of these datasets into pathways will greatly help to understand and to predict the responses of HSCs (and other stem cells) to various stimuli.

The clinical use of stem cells holds great promise, although the application of most classes of adult stem cells is either currently untested or is in the earliest phases of clinical testing.132,133 The only exception is HSCs, which have been used clinically since 1959 and are used increasingly routinely for transplantations, albeit almost exclusively in a non-pure form. By 1995, more than 40,000 transplants were performed annually world-wide.134,135 Currently the main indications for bone marrow transplantation are either hematopoietic cancers (leukemias and lymphomas), or the use of high-dose chemotherapy for non-hematopoietic malignancies (cancers in other organs). Other indications include diseases that involve genetic or acquired bone marrow failure, such as aplastic anemia, thalassemia sickle cell anemia, and increasingly, autoimmune diseases.

Transplantation of bone marrow and HSCs are carried out in two rather different settings, autologous and allogeneic. Autologous transplantations employ a patient's own bone marrow tissue and thus present no tissue incompatibility between the donor and the host. Allogeneic transplantations occur between two individuals who are not genetically identical (with the rare exceptions of transplantations between identical twins, often referred to as syngeneic transplantations). Non-identical individuals differ in their human leukocyte antigens (HLAs), proteins that are expressed by their white blood cells. The immune system uses these HLAs to distinguish between quot;selfquot; and quot;nonself.quot; For successful transplantation, allogeneic grafts must match most, if not all, of the six to ten major HLA antigens between host and donor. Even if they do, however, enough differences remain in mostly uncharacterized minor antigens to enable immune cells from the donor and the host to recognize the other as quot;nonself.quot; This is an important issue, as virtually all HSC transplants are carried out with either non-purified, mixed cell populations (mobilized peripheral blood, cord blood, or bone marrow) or cell populations that have been enriched for HSCs (e.g., by column selection for CD34+ cells) but have not been fully purified. These mixed population grafts contain sufficient lymphoid cells to mount an immune response against host cells if they are recognized as quot;non-self.quot; The clinical syndrome that results from this quot;non-selfquot; response is known as graft-versus-host disease (GVHD).136

In contrast, autologous grafts use cells harvested from the patient and offer the advantage of not causing GVHD. The main disadvantage of an autologous graft in the treatment of cancer is the absence of a graft-versusleukemia (GVL) or graft-versus-tumor (GVT) response, the specific immunological recognition of host tumor cells by donor-immune effector cells present in the transplant. Moreover, the possibility exists for contamination with cancerous or pre-cancerous cells.

Allogeneic grafts also have disadvantages. They are limited by the availability of immunologically-matched donors and the possibility of developing potentially lethal GVHD. The main advantage of allogeneic grafts is the potential for a GVL response, which can be an important contribution to achieving and maintaining complete remission.137,138

Today, most grafts used in the treatment of patients consist of either whole or CD34+-enriched bone marrow or, more likely, mobilized peripheral blood. The use of highly purified hematopoietic stem cells as grafts is rare.5658 However, the latter have the advantage of containing no detectable contaminating tumor cells in the case of autologous grafts, therefore not inducing GVHD, or presumably GVL,139141in allogeneic grafts. While they do so less efficiently than lymphocyte-containing cell mixtures, HSCs alone can engraft across full allogeneic barriers (i.e., when transplanted from a donor who is a complete mismatch for both major and minor transplantation antigens).139141The use of donor lymphocyte infusions (DLI) in the context of HSC transplantation allows for the controlled addition of lymphocytes, if necessary, to obtain or maintain high levels of donor cells and/or to induce a potentially curative GVL-response.142,143 The main problems associated with clinical use of highly purified HSCs are the additional labor and costs144 involved in obtaining highly purified cells in sufficient quantities.

While the possibilities of GVL and other immune responses to malignancies remain the focus of intense interest, it is also clear that in many cases, less-directed approaches such as chemotherapy or irradiation offer promise. However, while high-dose chemotherapy combined with autologous bone marrow transplantation has been reported to improve outcome (usually measured as the increase in time to progression, or increase in survival time),145154 this has not been observed by other researchers and remains controversial.155161 The tumor cells present in autologous grafts may be an important limitation in achieving long-term disease-free survival. Only further purification/ purging of the grafts, with rigorous separation of HSCs from cancer cells, can overcome this limitation. Initial small scale trials with HSCs purified by flow cytometry suggest that this is both possible and beneficial to the clinical outcome.56 In summary, purification of HSCs from cancer/lymphoma/leukemia patients offers the only possibility of using these cells post-chemotherapy to regenerate the host with cancer-free grafts. Purification of HSCs in allotransplantation allows transplantation with cells that regenerate the blood-forming system but cannot induce GVHD.

An important recent advance in the clinical use of HSCs is the development of non-myeloablative preconditioning regimens, sometimes referred to as quot;mini transplants.quot;162164 Traditionally, bone marrow or stem cell transplantation has been preceded by a preconditioning regimen consisting of chemotherapeutic agents, often combined with irradiation, that completely destroys host blood and bone marrow tissues (a process called myeloablation). This creates quot;spacequot; for the incoming cells by freeing stem cell niches and prevents an undesired immune response of the host cells against the graft cells, which could result in graft failure. However, myeloablation immunocompromises the patient severely and necessitates a prolonged hospital stay under sterile conditions. Many protocols have been developed that use a more limited and targeted approach to preconditioning. These nonmyeloablative preconditioning protocols, which combine excellent engraftment results with the ability to perform hematopoietic cell transplantation on an outpatient basis, have greatly changed the clinical practice of bone marrow transplantation.

FACS purification of HSCs in mouse and man completely eliminates contaminating T cells, and thus GVHD (which is caused by T-lymphocytes) in allogeneic transplants. Many HSC transplants have been carried out in different combinations of mouse strains. Some of these were matched at the major transplantation antigens but otherwise different (Matched Unrelated Donors or MUD); in others, no match at the major or minor transplantation antigens was expected. To achieve rapid and sustained engraftment, higher doses of HSCs were required in these mismatched allogeneic transplants than in syngeneic transplants.139141,165167 In these experiments, hosts whose immune and blood-forming systems were generated from genetically distinct donors were permanently capable of accepting organ transplants (such as the heart) from either donor or host, but not from mice unrelated to the donor or host. This phenomenon is known as transplant-induced tolerance and was observed whether the organ transplants were given the same day as the HSCs or up to one year later.139,166Hematopoietic cell transplant-related complications have limited the clinical application of such tolerance induction for solid organ grafts, but the use of non-myeloablative regimens to prepare the host, as discussed above, should significantly reduce the risk associated with combined HSC and organ transplants. Translation of these findings to human patients should enable a switch from chronic immunosuppression to prevent rejection to protocols wherein a single conditioning dose allows permanent engraftment of both the transplanted blood system and solid organ(s) or other tissue stem cells from the same donor. This should eliminate both GVHD and chronic host transplant immunosuppression, which lead to many complications, including life-threatening opportunistic infections and the development of malignant neoplasms.

We now know that several autoimmune diseasesdiseases in which immune cells attack normal body tissuesinvolve the inheritance of high risk-factor genes.168 Many of these genes are expressed only in blood cells. Researchers have recently tested whether HSCs could be used in mice with autoimmune disease (e.g., type 1 diabetes) to replace an autoimmune blood system with one that lacks the autoimmune risk genes. The HSC transplants cured mice that were in the process of disease development when nonmyeloablative conditioning was used for transplant.169 It has been observed that transplant-induced tolerance allows co-transplantation of pancreatic islet cells to replace destroyed islets.170 If these results using nonmyeloablative conditioning can be translated to humans, type 1 diabetes and several other autoimmune diseases may be treatable with pure HSC grafts. However, the reader should be cautioned that the translation of treatments from mice to humans is often complicated and time-consuming.

Banking is currently a routine procedure for UCB samples. If expansion of fully functional HSCs in tissue culture becomes a reality, HSC transplants may be possible by starting with small collections of HSCs rather than massive numbers acquired through mobilization and apheresis. With such a capability, collections of HSCs from volunteer donors or umbilical cords could be theoretically converted into storable, expandable stem cell banks useful on demand for clinical transplantation and/or for protection against radiation accidents. In mice, successful HSC transplants that regenerate fully normal immune and blood-forming systems can be accomplished when there is only a partial transplantation antigen match. Thus, the establishment of useful human HSC banks may require a match between as few as three out of six transplantation antigens (HLA). This might be accomplished with stem cell banks of as few as 4,00010,000 independent samples.

Leukemias are proliferative diseases of the hematopoietic system that fail to obey normal regulatory signals. They derive from stem cells or progenitors of the hematopoietic system and almost certainly include several stages of progression. During this progression, genetic and/or epigenetic changes occur, either in the DNA sequence itself (genetic) or other heritable modifications that affect the genome (epigenetic). These (epi)genetic changes alter cells from the normal hematopoietic system into cells capable of robust leukemic growth. There are a variety of leukemias, usually classified by the predominant pathologic cell types and/or the clinical course of the disease. It has been proposed that these are diseases in which self-renewing but poorly regulated cells, so-called "leukemia stem cells" (LSCs), are the populations that harbor all the genetic and epigenetic changes that allow leukemic progression.171176 While their progeny may be the characteristic cells observed with the leukemia, these progeny cells are not the self-renewing "malignant" cells of the disease. In this view, the events contributing to tumorigenic transformation, such as interrupted or decreased expression of "tumor suppressor" genes, loss of programmed death pathways, evasion of immune cells and macrophage surveillance mechanisms, retention of telomeres, and activation or amplification of self-renewal pathways, occur as single, rare events in the clonal progression to blast-crisis leukemia. As LT HSCs are the only selfrenewing cells in the myeloid pathway, it has been proposed that most, if not all, progression events occur at this level of differentiation, creating clonal cohorts of HSCs with increasing malignancy (see Figure 2.6). In this disease model, the final event, explosive selfrenewal, could occur at the level of HSC or at any of the known progenitors (see Figures 2.5 and 2.6). Activation of the -catenin/lef-tcf signal transduction and transcription pathway has been implicated in leukemic stem cell self-renewal in mouse AML and human CML.177 In both cases, the granulocyte-macrophage progenitors, not the HSCs or progeny blast cells, are the malignant self-renewing entities. In other models, such as the JunB-deficient tumors in mice and in chronic-phase CML in humans, the leukemic stem cell is the HSC itself.90,177 However, these HSCs still respond to regulatory signals, thus representing steps in the clonal progression toward blast crisis (see Figure 2.6).

Figure 2.6. Leukemic progression at the hematopoietic stem cell level. Self-renewing HSCs are the cells present long enough to accumulate the many activating events necessary for full transformation into tumorigenic cells. Under normal conditions, half of the offspring of HSC cell divisions would be expected to undergo differentiation, leaving the HSC pool stable in size. (A) (Pre) leukemic progression results in cohorts of HSCs with increasing malignant potential. The cells with the additional event (two events are illustrated, although more would be expected to occur) can outcompete less-transformed cells in the HSC pool if they divide faster (as suggested in the figure) or are more resistant to differentiation or apoptosis (cell death), two major exit routes from the HSC pool. (B) Normal HSCs differentiate into progenitors and mature cells; this is linked with limited proliferation (left). Partially transformed HSCs can still differentiate into progenitors and mature cells, but more cells are produced. Also, the types of mature cells that are produced may be skewed from the normal ratio. Fully transformed cells may be completely blocked in terminal differentiation, and large numbers of primitive blast cells, representing either HSCs or self-renewing, transformed progenitor cells, can be produced. While this sequence of events is true for some leukemias (e.g., AML), not all of the events occur in every leukemia. As with non-transformed cells, most leukemia cells (other than the leukemia stem cells) can retain the potential for (limited) differentiation.

Many methods have revealed contributing protooncogenes and lost tumor suppressors in myeloid leukemias. Now that LSCs can be isolated, researchers should eventually be able to assess the full sequence of events in HSC clones undergoing leukemic transformation. For example, early events, such as the AML/ETO translocation in AML or the BCR/ABL translocation in CML can remain present in normal HSCs in patients who are in remission (e.g., without detectable cancer).177,178 The isolation of LSCs should enable a much more focused attack on these cells, drawing on their known gene expression patterns, the mutant genes they possess, and the proteomic analysis of the pathways altered by the proto-oncogenic events.173,176,179 Thus, immune therapies for leukemia would become more realistic, and approaches to classify and isolate LSCs in blood could be applied to search for cancer stem cells in other tissues.180

After more than 50 years of research and clinical use, hematopoietic stem cells have become the best-studied stem cells and, more importantly, hematopoietic stem cells have seen widespread clinical use. Yet the study of HSCs remains active and continues to advance very rapidly. Fueled by new basic research and clinical discoveries, HSCs hold promise for such indications as treating autoimmunity, generating tolerance for solid organ transplants, and directing cancer therapy. However, many challenges remain. The availability of (matched) HSCs for all of the potential applications continues to be a major hurdle. Efficient expansion of HSCs in culture remains one of the major research goals. Future developments in genomics and proteomics, as well as in gene therapy, have the potential to widen the horizon for clinical application of hematopoietic stem cells even further.

Notes:

* Cellerant Therapeutics, 1531 Industrial Road, San Carlos, CA 94070. Current address: Department of Surgery, Arizona Health Sciences Center, 1501 N. Campbell Avenue, P.O. Box 245071, Tucson, AZ 857245071,e-mail: jdomen@surgery.arizona.edu.

** Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, E-mail: Amy_Wagers@harvard.edu

*** Director, Institute for Cancer/Stem Cell Biology and Medicine, Professor of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, Irv@stanford.edu.

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Bone Marrow (Hematopoietic) Stem Cells | stemcells.nih.gov

Bone Marrow Stem Cells Comments Off on Bone Marrow (Hematopoietic) Stem Cells | stemcells.nih.gov | September 28th, 2016

The transplantation of neural stem/progenitor cells (NPCs) is a promising therapeutic strategy for spinal cord injury (SCI). However, to date NPC transplantation has exhibited only limited success in the treatment of chronic SCI. Here, we show that chondroitin sulfate proteoglycans (CSPGs) in the glial scar around the site of chronic SCI negatively influence the long-term survival and integration of transplanted NPCs and their therapeutic potential for promoting functional repair and plasticity. We targeted CSPGs in the chronically injured spinal cord by sustained infusion of chondroitinase ABC (ChABC). One week later, the same rats were treated with transplants of NPCs and transient infusion of growth factors, EGF, bFGF, and PDGF-AA. We demonstrate that perturbing CSPGs dramatically optimizes NPC transplantation in chronic SCI. Engrafted NPCs successfully integrate and extensively migrate within the host spinal cord and principally differentiate into oligodendrocytes. Furthermore, this combined strategy promoted the axonal integrity and plasticity of the corticospinal tract and enhanced the plasticity of descending serotonergic pathways. These neuroanatomical changes were also associated with significantly improved neurobehavioral recovery after chronic SCI. Importantly, this strategy did not enhance the aberrant synaptic connectivity of pain afferents, nor did it exacerbate posttraumatic neuropathic pain. For the first time, we demonstrate key biological and functional benefits for the combined use of ChABC, growth factors, and NPCs to repair the chronically injured spinal cord. These findings could potentially bring us closer to the application of NPCs for patients suffering from chronic SCI or other conditions characterized by the formation of a glial scar.

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Synergistic effects of transplanted adult neural stem ...

Spinal Cord Stem Cells Comments Off on Synergistic effects of transplanted adult neural stem … | September 27th, 2016

GETTY

They suffer many complications in addition to paralysis and numbness and some of these problems are caused by a lack of the neurotransmitter GABA in the injured spinal cord.

A new University of California, San Francisco study in mice found human embryonic stem cells reduced two of the most severe side effects - incontinence and pain sensitivity.

Co-first author Assistant Professor Dr Cory Nicholas said: Chronic pain and bladder dysfunction remain significant quality-of-life issues for many people with spinal cord injuries.

Inhibitory cell-based neuro-therapy is a new approach and has shown promise to date in early animal studies, warranting further development."

The stem cell treatment differentiated into medial ganglionic eminence (MGE)-like cells, which produce GABA (gamma-Aminobutyric acid), an inhibitory neurotransmitter that is found throughout the central nervous system.

Our hope is that this treatment would last a long time, or maybe even be permanent

Dr Thomas Fandel

It plays an important role in reducing the excitability of neurons by binding to receptors that act on synapses.

Neuropathic pain and bladder dysfunction are at least in part attributed to overactive spinal cord circuits.

GETTY

Senior author Professor Dr Arnold Kriegstein said: We reasoned if we could take inhibitory neurons and directly place them into the spinal cord in the regions that are overactive, they might integrate into those circuits and suppress the activity.

In the study researchers used GABAergic inhibitory neuron precursors called MGE-like cells that were derived from human embryonic stem cells.

The neural precursor cells were placed into the spinal cords of mice two weeks after injury had been induced, where they could differentiate into GABA-producing neuron subtypes and form synaptic connections.

Co-author Dr Thomas Fandel, a research specialist at UCSF added: Rather than implanting these cells into the site of injury, at the mid-thoracic level, we injected them in the lumbosacral region, where the circuits are known to be overactive.

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Six months later we could see broad dispersion of the cells in that area. They were integrated into the spinal cord.

Tests showed the mice were not incontinent and had significantly reduced pain sensitivities.

Current treatments for neuropathic pain in people with spinal cord injuries most often involve opioids and other pain medications, as well as certain antidepressants, which have many side effects and tend to have limited efficacy.

Treatments for bladder dysfunction are often anticholinergics, but these drugs have side effects like dizziness and dry mouth.

GETTY

Botox may help with bladder spasms, but the benefits tend to be transient.

Dr Fandel added: The current approaches for treatment are not very effective and clearly more options are needed.

Our hope is that this treatment would last a long time, or maybe even be permanent.

The study was published in the journal Cell Stem Cell.

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Human stem cells could provide relief for spinal cord ...

Spinal Cord Stem Cells Comments Off on Human stem cells could provide relief for spinal cord … | September 26th, 2016

SAN FRANCISCO Researchers have successfully transplanted healthy human cells into mice with spinal cord injuries, bringing the world one step closer to easing the chronic pain and incontinence suffered by people with paralysis.

The research team did not focus on restoring the rodents ability to walk; rather, it helped remedy these two other debilitating side effects of spinal cord injury.

If successful in humans, thefindingscould someday ease the lives of those with these distressing conditions, said Dr. Arnold Kriegstein, co-senior author of the study and director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UC San Francisco. The research was published in Thursdays issue of the journal Cell Stem Cell.

This is a very important step, Kriegstein said. The treated animals improved in pain relief and bladder function.The research offers the promising potential of using a new therapeutic approach cell therapy to repair damaged neural tissue, showing that new cells can be integrated into an injured spinal cord.

A similar approach also has helped mice with epilepsy and Parkinsons disease.

More than aquarter of a million Americans live with spinal cord injuries, and 17,000 new cases occur each year, according to the National Spinal Cord Injury Statistical Center. More than half of those people go on to develop chronic pain in their limbs, called neuropathy. And nearly all develop bladder problems, which can result in kidney damage.

The spinal cord is the major highway for nerve cells to relay information between the brain and the rest of the body. When the spinal cord is injured, tears and inflammation harm surrounding cells.

The field has been very focused on restoring patients ability to walk, perhaps because thats often their most visible impairment, study co-authorLinda Noble-Haeusslein, a professor of physical therapy and rehabilitation at UCSF, said in a statement.

But a recent study showing that patients complained of pain and loss of bladder control more than paralysis suggested that we had really missed the boat as a field, she said. It caused us to dramatically shift what we do in the lab.

The cells used in the study, called neurons, were grown from human embryonic stem cells the bodys building blocks, capable of generating more than1,000 different types of adult cells.

They arent just any garden-variety neuron. These cells have the ability to inhibit, rather than excite, the neural network of the spine. Thats important because the pain and loss of bladder control are believed to be caused by overactivated neural circuits.

The healthy body keeps this excitable circuitry under control.But inflammation caused by a spinal cord injury causes a loss of this control.

The UCSF team grew the replacement cells in a South San Francisco biotech lab ofNeurona Therapeutics, founded by study co-authorCory Nicholasand Kriegstein, UCSFprofessor of developmental and stem cell biology. The company hopes to mass-produce these cells for use in future clinical trials.

They injected the young human cells into the spines of mice about two weeks afterinjury. They targeted the thoracic region about halfway up the spinal cord because thats a common site of injury for humans.But they were careful not to inject the young cells directly into the injured areas because that is a toxic place full of inflammation.

Remarkably, over the next six months the human cells matured, migrated toward the site of the injury and made connections with the spinal cords of the mice.

Compared to untreated mice, the treated rodents showed significantly less hypersensitivity to touch and painful stimuli and reduced abnormal scratching. Treated mice also had improved bladder function and produced more normal, voluntary patterns of urination in their cages.

A different research team is focusing on a fix for paralysis. This necessitatesa different strategy, requiring treatment with stem cell-derived neurons whose job it is to conduct electrical impulses down the spine. And these cells may face a more daunting environment if injected directly into injured areas.

The first trial by Geron Corp. stalled in late 2011, mostly because of financial concerns. But a Fremont-based biotech company calledAsterias Biotherapeutics, a subsidiary of BioTime, bought Gerons intellectual property and is continuing the research. It recently received approval fromthe U.S. Food and Drug Administration for a safety and early trial of the cells for treating spinal cord injury.

Meanwhile, the UCSF team is working to replicate their findings of improved bladder control and chronic pain. And they seek to learn the best time to inject the cells. Funders for the research included the National Institutes of Health and the California Institute of Regenerative Medicine.

The team is hoping to scale up their production of their specialized cells with the goal of entering human trials, after proving to the FDA that their effort is safe.

We are eager to move in that direction as quickly as we can, Kriegstein said.

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spinal cord injury, embryonic stem cells, paralysis, pain ...

Spinal Cord Stem Cells Comments Off on spinal cord injury, embryonic stem cells, paralysis, pain … | September 26th, 2016

Track-1 Cell Therapy:

Cell therapyas performed by alternativemedicinepractitioners is very different from the controlled research done by conventionalstem cellmedical researchers. Alternative practitioners refer to their form of cell therapy by several other different names includingxenotransplanttherapy,glandular therapy, and fresh cell therapy. Proponents ofcell therapyclaim that it has been used successfully to rebuild damaged cartilage in joints, repair spinal cord injuries,strengthen a weakenedimmune system, treat autoimmune diseases such as AIDS, and help patients withneurological disorderssuch as Alzheimers disease,Parkinson's diseaseand epilepsy.

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Track-2 Gene therapy:

Gene therapyand cell therapy are overlapping fields of biomedical research with the goals of repairing the direct cause of genetic diseases in the DNA orcellularpopulation, respectively. The development of suitablegene therapytreatments for manygenetic diseasesand some acquired diseases has encountered many challenges and uncovered new insights into gene interactions and regulation. Further development often involves uncovering basic scientific knowledge of the affected tissues, cells, and genes, as well as redesigning vectors, formulations, and regulatory cassettes for the genes.Cell therapyis expanding its repertoire of cell types for administration.Cell therapytreatment strategies include isolation and transfer of specific stem cell populations, administration of effector cells, and induction of mature cells to becomepluripotent cells, and reprogramming of mature cells.

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Track-3 Cell and gene therapy products:

Articles containing or consisting ofhuman cellsor tissues that are intended for implantation,transplantation, infusion, or transfer to a human recipient.Gene therapiesare novel and complex products that can offer unique challenges in product development. Hence, ongoing communication between the FDA and stakeholders is essential to meet these challenges.Gene therapy productsare being developed around the world, the FDA is engaged in a number of international harmonization activities in this area.

Examples:Musculoskeletal tissue, skin, ocular tissue, human heart valves;vascular graft, dura mater, reproductive tissue/cells, Stem/progenitor cells,somatic cells, Cells transduced withgene therapyvectors , Combination products (e.g., cells or tissue + device)

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Track-4 Cellular therapy:

Cellular therapy, also calledlive cell therapy, cellular suspensions, glandular therapy, fresh cell therapy, sick cell therapy,embryonic cell therapy, andorgan therapy- refers to various procedures in which processed tissue from animal embryos, foetuses or organs, is injected or taken orally. Products are obtained from specific organs or tissues said to correspond with the unhealthy organs or tissues of the recipient. Proponents claim that the recipient's body automatically transports the injected cells to thetarget organs, where they supposedly strengthen them and regenerate their structure. The organs and glands used in cell treatment include brain, pituitary,thyroid, adrenals, thymus, liver,kidney, pancreas, spleen, heart,ovary, testis, and parotid. Several different types of cell or cell extract can be given simultaneously - some practitioners routinely give up to 20 or more at once.

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Track-5 Cancer gene therapy:

Cancer therapiesare drugs or other substances that block the growth and spread ofcancerby interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread ofcancer. Many cancer therapies have been approved by the Food and Drug Administration (FDA) to treat specific types of cancer. The development of targetedtherapiesrequires the identification of good targets that is, targets that play a key role in cancer cell growth and survival. One approach to identify potential targets is to compare the amounts of individualproteinsin cancer cells with those in normal cells.Proteinsthat are present in cancer cells but not normal cells or that are more abundant incancercells would be potential targets, especially if they are known to be involved incell growthor survival.

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Track-6 Nano therapy:

Nano Therapymay be defined as the monitoring, repair, construction and control of human biological systems at themolecular level, using engineerednanodevicesand nanostructures. Basic nanostructured materials, engineeredenzymes, and the many products of biotechnology will be enormously useful in near-term medical applications. However, the full promise ofnanomedicineis unlikely to arrive until after the development of precisely controlled or programmable medical Nano machines andnanorobots.

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Track-7 Skin cell therapy:

Stem cellshave newly become a huge catchphrase in theskincarebiosphere. Skincare specialists are not usingembryonic stem cells; it is impossible to integrate live materials into a skincare product. Instead, scientists are creating products with specialized peptides andenzymesor plantstem cellswhich, when applied topically on the surface, help to protect the human skinstem cellsfrom damage and deterioration or stimulate the skins own stem cells. Currently, the technique is mainly used to save the lives of patients who have third degree burns over very large areas of their bodies.

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Track-8 HIV gene therapy:

Highly activeantiretroviral therapydramatically improves survival inHIV-infected patients. However, persistence of HIV in reservoirs has necessitated lifelong treatment that can be complicated bycumulative toxicities, incomplete immune restoration, and the emergence of drug-resistant escapemutants. Cell and gene therapies offer the promise of preventing progressiveHIV infectionby interfering with HIV replication in the absence of chronicantiviral therapy.

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Track-9 Diabetes for gene therapy:

Cell therapyapproaches for this disease are focused on developing the most efficient methods for the isolation ofpancreasbeta cells or appropriatestem cells, appropriate location forcell transplant, and improvement of their survival upon infusion. Alternatively, gene andcell therapyscientists are developing methods to reprogram some of the other cells of the pancreas to secreteinsulin. Currently ongoingclinical trialsusing these gene andcell therapystrategies hold promise for improved treatments of type I diabetes in the future. The firstgene therapyapproach to diabetes was put forward shortly after the cloning of theinsulingene. It was proposed that non-insulin producing cells could be made into insulin-producingcells using a suitable promoter and insulin gene construct, and that these substitute cells could restore insulin production in type 1 and some type 2 diabetics.

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Track-10 Viral gene therapy:

Converting avirusinto a vector Theviral life cyclecan be divided into two temporally distinct phases: infection and replication. Forgene therapyto be successful, an appropriate amount of a therapeutic gene must be delivered into the target tissue without substantial toxicity. Eachviral vectorsystem is characterized by an inherent set of properties that affect its suitability for specific gene therapy applications. For some disorders, long-term expression from a relatively small proportion of cells would be sufficient (for example, genetic disorders), whereas otherpathologiesmight require high, but transient,gene expression. For example, gene therapies designed to interfere with a viral infectious process or inhibit the growth ofcancer cellsby reconstitution of inactivated tumour suppressor genes may require gene transfer into a large fraction of theabnormal cells.

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Track-11 Stem cell therapies:

Stem cells have tremendous promise to help us understand and treat a range of diseases, injuries and other health-related conditions. Their potential is evident in the use ofblood stem cellsto treat diseases of the blood, a therapy that has saved the lives of thousands of children withleukaemia; and can be seen in the use ofstem cellsfor tissue grafts to treat diseases or injury to the bone, skin and surface of the eye. Some bone, skin andcorneal(eye) injuries and diseases can be treated bygraftingor implanting tissues, and the healing process relies on stem cells within thisimplanted tissue.

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Track-12 Stem cell preservation:

The ability to preserve the cells is critical to theirclinicalapplication. It improves patient access to therapies by increasing the genetic diversity of cells available. In addition, the ability to preserve cells improves the "manufacturability" of acell therapyproduct by permitting the cells to be stored until the patient is ready for administration of the therapy, permitting inventory control of products, and improving management of staffing atcell therapyfacilities. Finally, the ability to preservecell therapiesimproves the safety of cell therapy products by extending the shelf life of a product and permitting completion of safety and quality control testing before release of the product for use. preservation permits coordination between the manufacture of the therapy and patient care regimes.

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Track-13 Stem cell products:

The globalstemcell,Stem cell productsmarket will grow from about $5.6 billion in 2013 to nearly $10.6 billion in 2018, registering a compound annual growth rate (CAGR) of 13.6% from 2013 through 2018.This trackdiscusses the implications ofstemcellresearchand commercial trends in the context of the current size and growth of thepharmaceutical market, both in global terms and analysed by the most important national markets.

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Track-14 Genetically inherited diseases:

Agenetic diseaseis any disease that is caused by an abnormality in an individual'sgenome, the person's entiregeneticmakeup. The abnormality can range from minuscule to major -- from a discrete mutation in a single base in the DNA of a single gene to a grosschromosome abnormalityinvolving the addition or subtraction of an entirechromosomeor set of chromosomes.Most genetic diseases are the direct result of a mutation in one gene. However, one of the most difficult problems ahead is to find out how genes contribute to diseases that have a complex pattern ofinheritance, such as in the cases of diabetes,asthma,cancerandmental illness. In all these cases, no one gene has the yes/no power to say whether a person has a disease or not. It is likely that more than one mutation is required before the disease is manifest, and a number of genes may each make a subtle contribution to a person's susceptibility to a disease; genes may also affect how a person reacts toenvironmental factors.

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Track-15 Plant stem cells:

Plantshave emerged as powerful production platforms for the expression of fully functional recombinantmammalian proteins. These expression systems have demonstrated the ability to produce complexglycoproteinsin a cost-efficient manner at large scale. The full realization of thetherapeuticpotential of stem cells has only recently come into the forefront ofregenerative medicine. Stem cells are unprogrammed cells that can differentiate into cells with specific functions.Regenerative therapiesare used to stimulate healing and might be used in the future to treat various kinds of diseases.Regenerative medicinewill result in an extended healthy life span. A fresh apple is a symbol for beautiful skin. Hair greying for example could be shown to result from the fact that themelanocyte stem cellsin the hair follicle have died off.

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Track-16 Plant stem cell rejuvenation:

Asplantscannot escape from danger by running or taking flight, they need a special mechanism to withstandenvironmental stress. What empowers them to withstand harsh attacks and preserve life is the stem cell. According to Wikipedia, plantstem cellsnever undergo theagingprocess but constantly create new specialized and unspecialized cells, and they have the potential to grow into any organ, tissue, or cell in the body. The everlasting life is due to the hormones auxin andgibberellin. British scientists found that plant stem cells were much more sensitive toDNAdamage than other cells. And once they sense damage, they trigger death of these cells.

Rejuvenate with Plant Stem Cells

Detoxifyand release toxins on a cellular level. Nourishyour body with vital nutrients. Regenerateyour cells and diminish the effects of aging.

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Track-17 Clinical trials in cell and gene therapy:

Aclinical trialis a research study that seeks to determine if a treatment is safe and effective. Advancing new cell andgene therapies(CGTs) from the laboratory into early-phaseclinical trialshas proven to be a complex task even for experienced investigators. Due to the wide variety ofCGTproducts and their potential applications, a case-by-case assessment is warranted for the design of each clinical trial.

Objectives:Determine thepharmacokineticsof this regimen by the persistence of modified T cells in the blood of these patients, Evaluate theimmunogenicityof murine sequences in chimeric anti-CEA Ig TCR, Assess immunologic parameters which correlate with the efficacy of this regimen in these patients, Evaluate, in a preliminary manner, the efficacy of this regimen in patients with CEA bearingtumours.

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Track-18 Molecular epigenetics:

Epigeneticsis the study of heritable changes in thephenotypeof a cell or organism that are not caused by its genotype. The molecular basis of anepigeneticprofile arises from covalent modifications of protein andDNAcomponents ofchromatin. The epigenetic profile of a cell often dictates cell fate, as well as mammalian development,agingand disease. Epigenetics has evolved to become the science that explains how the differences in the patterns ofgene expressionin diverse cells or tissues are executed and inherited.

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Track-19 Bioengineering therapeutics:

The goals ofbioengineeringstrategies for targetedcancertherapies are (1) to deliver a high dose of an anticancer drug directly to a cancer tumour, (2) to enhance drug uptake by malignant cells, and (3) to minimize drug uptake by non-malignant cells. In ESRD micro electro mechanical systems andnanotechnologyto create components such as robust silicon Nano pore filters that mimic natural kidney structure for high-efficiency toxin clearance. It also usestissue engineeringto build a miniature bioreactor in which immune-isolated human-derived renal cells perform key functions, such as reabsorption of water and salts.In drug delivery for a leading cause ofblindness, photo-etching fabrication techniques from themicrochipindustry to create thin-film and planar micro devices (dimensions in millionths of meters) with protectivemedicationreservoirs andnanopores(measured in billionths of meters) for insertion in the back of the eye to deliver sustained doses of drug across protective retinalepithelial tissuesover the course of several months.

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Track-20 Advanced gene therapy:

Advanced therapiesare different fromconventional medicines, which are made from chemicals or proteins.Gene-therapymedicines:these contain genes that lead to atherapeuticeffect. They work by inserting 'recombinant' genes into cells, usually to treat a variety of diseases, including genetic disorders, cancer or long-term diseases.Somatic-cell therapymedicines:these contain cells or tissues that have been manipulated to change their biological characteristics.Advanced Cell &Gene Therapyprovides guidanceinprocess development, GMP/GTP manufacturing,regulatory affairs, due diligence and strategy, specializing in cell therapy,gene therapy, and tissue-engineeredregenerative medicineproducts.

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Cell Therapy Conferences | Spain | Worldwide Events ...

Cardiac Stem Cells Comments Off on Cell Therapy Conferences | Spain | Worldwide Events … | September 23rd, 2016

Muscle is a soft tissue found in most animals. Muscle cells contain protein filaments of actin and myosin that slide past one another, producing a contraction that changes both the length and the shape of the cell. Muscles function to produce force and motion. They are primarily responsible for maintaining and changing posture, locomotion, as well as movement of internal organs, such as the contraction of the heart and the movement of food through the digestive system via peristalsis.

Muscle tissues are derived from the mesodermal layer of embryonic germ cells in a process known as myogenesis. There are three types of muscle, skeletal or striated, cardiac, and smooth. Muscle action can be classified as being either voluntary or involuntary. Cardiac and smooth muscles contract without conscious thought and are termed involuntary, whereas the skeletal muscles contract upon command.[1] Skeletal muscles in turn can be divided into fast and slow twitch fibers.

Muscles are predominantly powered by the oxidation of fats and carbohydrates, but anaerobic chemical reactions are also used, particularly by fast twitch fibers. These chemical reactions produce adenosine triphosphate (ATP) molecules that are used to power the movement of the myosin heads.[2]

The term muscle is derived from the Latin musculus meaning "little mouse" perhaps because of the shape of certain muscles or because contracting muscles look like mice moving under the skin.[3][4]

The anatomy of muscles includes gross anatomy, which comprises all the muscles of an organism, and microanatomy, which comprises the structures of a single muscle.

Muscle tissue is a soft tissue, and is one of the four fundamental types of tissue present in animals. There are three types of muscle tissue recognized in vertebrates:

Cardiac and skeletal muscles are "striated" in that they contain sarcomeres that are packed into highly regular arrangements of bundles; the myofibrils of smooth muscle cells are not arranged in sarcomeres and so are not striated. While the sarcomeres in skeletal muscles are arranged in regular, parallel bundles, cardiac muscle sarcomeres connect at branching, irregular angles (called intercalated discs). Striated muscle contracts and relaxes in short, intense bursts, whereas smooth muscle sustains longer or even near-permanent contractions.

Skeletal (voluntary) muscle is further divided into two broad types: slow twitch and fast twitch:

The density of mammalian skeletal muscle tissue is about 1.06kg/liter.[8] This can be contrasted with the density of adipose tissue (fat), which is 0.9196kg/liter.[9] This makes muscle tissue approximately 15% denser than fat tissue.

All muscles are derived from paraxial mesoderm. The paraxial mesoderm is divided along the embryo's length into somites, corresponding to the segmentation of the body (most obviously seen in the vertebral column.[10] Each somite has 3 divisions, sclerotome (which forms vertebrae), dermatome (which forms skin), and myotome (which forms muscle). The myotome is divided into two sections, the epimere and hypomere, which form epaxial and hypaxial muscles, respectively. The only epaxial muscles in humans are the erector spinae and small intervertebral muscles, and are innervated by the dorsal rami of the spinal nerves. All other muscles, including those of the limbs are hypaxial, and inervated by the ventral rami of the spinal nerves.[10]

During development, myoblasts (muscle progenitor cells) either remain in the somite to form muscles associated with the vertebral column or migrate out into the body to form all other muscles. Myoblast migration is preceded by the formation of connective tissue frameworks, usually formed from the somatic lateral plate mesoderm. Myoblasts follow chemical signals to the appropriate locations, where they fuse into elongate skeletal muscle cells.[10]

Skeletal muscles are sheathed by a tough layer of connective tissue called the epimysium. The epimysium anchors muscle tissue to tendons at each end, where the epimysium becomes thicker and collagenous. It also protects muscles from friction against other muscles and bones. Within the epimysium are multiple bundles called fascicles, each of which contains 10 to 100 or more muscle fibers collectively sheathed by a perimysium. Besides surrounding each fascicle, the perimysium is a pathway for nerves and the flow of blood within the muscle. The threadlike muscle fibers are the individual muscle cells (myocytes), and each cell is encased within its own endomysium of collagen fibers. Thus, the overall muscle consists of fibers (cells) that are bundled into fascicles, which are themselves grouped together to form muscles. At each level of bundling, a collagenous membrane surrounds the bundle, and these membranes support muscle function both by resisting passive stretching of the tissue and by distributing forces applied to the muscle.[11] Scattered throughout the muscles are muscle spindles that provide sensory feedback information to the central nervous system. (This grouping structure is analogous to the organization of nerves which uses epineurium, perineurium, and endoneurium).

This same bundles-within-bundles structure is replicated within the muscle cells. Within the cells of the muscle are myofibrils, which themselves are bundles of protein filaments. The term "myofibril" should not be confused with "myofiber", which is a simply another name for a muscle cell. Myofibrils are complex strands of several kinds of protein filaments organized together into repeating units called sarcomeres. The striated appearance of both skeletal and cardiac muscle results from the regular pattern of sarcomeres within their cells. Although both of these types of muscle contain sarcomeres, the fibers in cardiac muscle are typically branched to form a network. Cardiac muscle fibers are interconnected by intercalated discs,[12] giving that tissue the appearance of a syncytium.

The filaments in a sarcomere are composed of actin and myosin.

The gross anatomy of a muscle is the most important indicator of its role in the body. There is an important distinction seen between pennate muscles and other muscles. In most muscles, all the fibers are oriented in the same direction, running in a line from the origin to the insertion. However, In pennate muscles, the individual fibers are oriented at an angle relative to the line of action, attaching to the origin and insertion tendons at each end. Because the contracting fibers are pulling at an angle to the overall action of the muscle, the change in length is smaller, but this same orientation allows for more fibers (thus more force) in a muscle of a given size. Pennate muscles are usually found where their length change is less important than maximum force, such as the rectus femoris.

Skeletal muscle is arranged in discrete muscles, an example of which is the biceps brachii (biceps). The tough, fibrous epimysium of skeletal muscle is both connected to and continuous with the tendons. In turn, the tendons connect to the periosteum layer surrounding the bones, permitting the transfer of force from the muscles to the skeleton. Together, these fibrous layers, along with tendons and ligaments, constitute the deep fascia of the body.

The muscular system consists of all the muscles present in a single body. There are approximately 650 skeletal muscles in the human body,[13] but an exact number is difficult to define. The difficulty lies partly in the fact that different sources group the muscles differently and partly in that some muscles, such as palmaris longus, are not always present.

A muscular slip is a narrow length of muscle that acts to augment a larger muscle or muscles.

The muscular system is one component of the musculoskeletal system, which includes not only the muscles but also the bones, joints, tendons, and other structures that permit movement.

The three types of muscle (skeletal, cardiac and smooth) have significant differences. However, all three use the movement of actin against myosin to create contraction. In skeletal muscle, contraction is stimulated by electrical impulses transmitted by the nerves, the motoneurons (motor nerves) in particular. Cardiac and smooth muscle contractions are stimulated by internal pacemaker cells which regularly contract, and propagate contractions to other muscle cells they are in contact with. All skeletal muscle and many smooth muscle contractions are facilitated by the neurotransmitter acetylcholine.

The action a muscle generates is determined by the origin and insertion locations. The cross-sectional area of a muscle (rather than volume or length) determines the amount of force it can generate by defining the number of sarcomeres which can operate in parallel.[citation needed] The amount of force applied to the external environment is determined by lever mechanics, specifically the ratio of in-lever to out-lever. For example, moving the insertion point of the biceps more distally on the radius (farther from the joint of rotation) would increase the force generated during flexion (and, as a result, the maximum weight lifted in this movement), but decrease the maximum speed of flexion. Moving the insertion point proximally (closer to the joint of rotation) would result in decreased force but increased velocity. This can be most easily seen by comparing the limb of a mole to a horse - in the former, the insertion point is positioned to maximize force (for digging), while in the latter, the insertion point is positioned to maximize speed (for running).

Muscular activity accounts for much of the body's energy consumption. All muscle cells produce adenosine triphosphate (ATP) molecules which are used to power the movement of the myosin heads. Muscles have a short-term store of energy in the form of creatine phosphate which is generated from ATP and can regenerate ATP when needed with creatine kinase. Muscles also keep a storage form of glucose in the form of glycogen. Glycogen can be rapidly converted to glucose when energy is required for sustained, powerful contractions. Within the voluntary skeletal muscles, the glucose molecule can be metabolized anaerobically in a process called glycolysis which produces two ATP and two lactic acid molecules in the process (note that in aerobic conditions, lactate is not formed; instead pyruvate is formed and transmitted through the citric acid cycle). Muscle cells also contain globules of fat, which are used for energy during aerobic exercise. The aerobic energy systems take longer to produce the ATP and reach peak efficiency, and requires many more biochemical steps, but produces significantly more ATP than anaerobic glycolysis. Cardiac muscle on the other hand, can readily consume any of the three macronutrients (protein, glucose and fat) aerobically without a 'warm up' period and always extracts the maximum ATP yield from any molecule involved. The heart, liver and red blood cells will also consume lactic acid produced and excreted by skeletal muscles during exercise.

At rest, skeletal muscle consumes 54.4 kJ/kg(13.0kcal/kg) per day. This is larger than adipose tissue (fat) at 18.8kJ/kg (4.5kcal/kg), and bone at 9.6kJ/kg (2.3kcal/kg).[14]

The efferent leg of the peripheral nervous system is responsible for conveying commands to the muscles and glands, and is ultimately responsible for voluntary movement. Nerves move muscles in response to voluntary and autonomic (involuntary) signals from the brain. Deep muscles, superficial muscles, muscles of the face and internal muscles all correspond with dedicated regions in the primary motor cortex of the brain, directly anterior to the central sulcus that divides the frontal and parietal lobes.

In addition, muscles react to reflexive nerve stimuli that do not always send signals all the way to the brain. In this case, the signal from the afferent fiber does not reach the brain, but produces the reflexive movement by direct connections with the efferent nerves in the spine. However, the majority of muscle activity is volitional, and the result of complex interactions between various areas of the brain.

Nerves that control skeletal muscles in mammals correspond with neuron groups along the primary motor cortex of the brain's cerebral cortex. Commands are routed though the basal ganglia and are modified by input from the cerebellum before being relayed through the pyramidal tract to the spinal cord and from there to the motor end plate at the muscles. Along the way, feedback, such as that of the extrapyramidal system contribute signals to influence muscle tone and response.

Deeper muscles such as those involved in posture often are controlled from nuclei in the brain stem and basal ganglia.

The afferent leg of the peripheral nervous system is responsible for conveying sensory information to the brain, primarily from the sense organs like the skin. In the muscles, the muscle spindles convey information about the degree of muscle length and stretch to the central nervous system to assist in maintaining posture and joint position. The sense of where our bodies are in space is called proprioception, the perception of body awareness. More easily demonstrated than explained, proprioception is the "unconscious" awareness of where the various regions of the body are located at any one time. This can be demonstrated by anyone closing their eyes and waving their hand around. Assuming proper proprioceptive function, at no time will the person lose awareness of where the hand actually is, even though it is not being detected by any of the other senses.

Several areas in the brain coordinate movement and position with the feedback information gained from proprioception. The cerebellum and red nucleus in particular continuously sample position against movement and make minor corrections to assure smooth motion.

The efficiency of human muscle has been measured (in the context of rowing and cycling) at 18% to 26%. The efficiency is defined as the ratio of mechanical work output to the total metabolic cost, as can be calculated from oxygen consumption. This low efficiency is the result of about 40% efficiency of generating ATP from food energy, losses in converting energy from ATP into mechanical work inside the muscle, and mechanical losses inside the body. The latter two losses are dependent on the type of exercise and the type of muscle fibers being used (fast-twitch or slow-twitch). For an overall efficiency of 20 percent, one watt of mechanical power is equivalent to 4.3 kcal per hour. For example, one manufacturer of rowing equipment calibrates its rowing ergometer to count burned calories as equal to four times the actual mechanical work, plus 300 kcal per hour,[15] this amounts to about 20 percent efficiency at 250 watts of mechanical output. The mechanical energy output of a cyclic contraction can depend upon many factors, including activation timing, muscle strain trajectory, and rates of force rise & decay. These can be synthesized experimentally using work loop analysis.

A display of "strength" (e.g. lifting a weight) is a result of three factors that overlap: physiological strength (muscle size, cross sectional area, available crossbridging, responses to training), neurological strength (how strong or weak is the signal that tells the muscle to contract), and mechanical strength (muscle's force angle on the lever, moment arm length, joint capabilities).

Vertebrate muscle typically produces approximately 2533N (5.67.4lbf) of force per square centimeter of muscle cross-sectional area when isometric and at optimal length.[16] Some invertebrate muscles, such as in crab claws, have much longer sarcomeres than vertebrates, resulting in many more sites for actin and myosin to bind and thus much greater force per square centimeter at the cost of much slower speed. The force generated by a contraction can be measured non-invasively using either mechanomyography or phonomyography, be measured in vivo using tendon strain (if a prominent tendon is present), or be measured directly using more invasive methods.

The strength of any given muscle, in terms of force exerted on the skeleton, depends upon length, shortening speed, cross sectional area, pennation, sarcomere length, myosin isoforms, and neural activation of motor units. Significant reductions in muscle strength can indicate underlying pathology, with the chart at right used as a guide.

Since three factors affect muscular strength simultaneously and muscles never work individually, it is misleading to compare strength in individual muscles, and state that one is the "strongest". But below are several muscles whose strength is noteworthy for different reasons.

Humans are genetically predisposed with a larger percentage of one type of muscle group over another. An individual born with a greater percentage of Type I muscle fibers would theoretically be more suited to endurance events, such as triathlons, distance running, and long cycling events, whereas a human born with a greater percentage of Type II muscle fibers would be more likely to excel at sprinting events such as 100 meter dash.[citation needed]

Exercise is often recommended as a means of improving motor skills, fitness, muscle and bone strength, and joint function. Exercise has several effects upon muscles, connective tissue, bone, and the nerves that stimulate the muscles. One such effect is muscle hypertrophy, an increase in size. This is used in bodybuilding.

Various exercises require a predominance of certain muscle fiber utilization over another. Aerobic exercise involves long, low levels of exertion in which the muscles are used at well below their maximal contraction strength for long periods of time (the most classic example being the marathon). Aerobic events, which rely primarily on the aerobic (with oxygen) system, use a higher percentage of Type I (or slow-twitch) muscle fibers, consume a mixture of fat, protein and carbohydrates for energy, consume large amounts of oxygen and produce little lactic acid. Anaerobic exercise involves short bursts of higher intensity contractions at a much greater percentage of their maximum contraction strength. Examples of anaerobic exercise include sprinting and weight lifting. The anaerobic energy delivery system uses predominantly Type II or fast-twitch muscle fibers, relies mainly on ATP or glucose for fuel, consumes relatively little oxygen, protein and fat, produces large amounts of lactic acid and can not be sustained for as long a period as aerobic exercise. Many exercises are partially aerobic and partially anaerobic; for example, soccer and rock climbing involve a combination of both.

The presence of lactic acid has an inhibitory effect on ATP generation within the muscle; though not producing fatigue, it can inhibit or even stop performance if the intracellular concentration becomes too high. However, long-term training causes neovascularization within the muscle, increasing the ability to move waste products out of the muscles and maintain contraction. Once moved out of muscles with high concentrations within the sarcomere, lactic acid can be used by other muscles or body tissues as a source of energy, or transported to the liver where it is converted back to pyruvate. In addition to increasing the level of lactic acid, strenuous exercise causes the loss of potassium ions in muscle and causing an increase in potassium ion concentrations close to the muscle fibres, in the interstitium. Acidification by lactic acid may allow recovery of force so that acidosis may protect against fatigue rather than being a cause of fatigue.[18]

Delayed onset muscle soreness is pain or discomfort that may be felt one to three days after exercising and generally subsides two to three days later. Once thought to be caused by lactic acid build-up, a more recent theory is that it is caused by tiny tears in the muscle fibers caused by eccentric contraction, or unaccustomed training levels. Since lactic acid disperses fairly rapidly, it could not explain pain experienced days after exercise.[19]

Independent of strength and performance measures, muscles can be induced to grow larger by a number of factors, including hormone signaling, developmental factors, strength training, and disease. Contrary to popular belief, the number of muscle fibres cannot be increased through exercise. Instead, muscles grow larger through a combination of muscle cell growth as new protein filaments are added along with additional mass provided by undifferentiated satellite cells alongside the existing muscle cells.[13]

Biological factors such as age and hormone levels can affect muscle hypertrophy. During puberty in males, hypertrophy occurs at an accelerated rate as the levels of growth-stimulating hormones produced by the body increase. Natural hypertrophy normally stops at full growth in the late teens. As testosterone is one of the body's major growth hormones, on average, men find hypertrophy much easier to achieve than women. Taking additional testosterone or other anabolic steroids will increase muscular hypertrophy.

Muscular, spinal and neural factors all affect muscle building. Sometimes a person may notice an increase in strength in a given muscle even though only its opposite has been subject to exercise, such as when a bodybuilder finds her left biceps stronger after completing a regimen focusing only on the right biceps. This phenomenon is called cross education.[citation needed]

Inactivity and starvation in mammals lead to atrophy of skeletal muscle, a decrease in muscle mass that may be accompanied by a smaller number and size of the muscle cells as well as lower protein content.[20] Muscle atrophy may also result from the natural aging process or from disease.

In humans, prolonged periods of immobilization, as in the cases of bed rest or astronauts flying in space, are known to result in muscle weakening and atrophy. Atrophy is of particular interest to the manned spaceflight community, because the weightlessness experienced in spaceflight results is a loss of as much as 30% of mass in some muscles.[21][22] Such consequences are also noted in small hibernating mammals like the golden-mantled ground squirrels and brown bats.[23]

During aging, there is a gradual decrease in the ability to maintain skeletal muscle function and mass, known as sarcopenia. The exact cause of sarcopenia is unknown, but it may be due to a combination of the gradual failure in the "satellite cells" that help to regenerate skeletal muscle fibers, and a decrease in sensitivity to or the availability of critical secreted growth factors that are necessary to maintain muscle mass and satellite cell survival. Sarcopenia is a normal aspect of aging, and is not actually a disease state yet can be linked to many injuries in the elderly population as well as decreasing quality of life.[24]

There are also many diseases and conditions that cause muscle atrophy. Examples include cancer and AIDS, which induce a body wasting syndrome called cachexia. Other syndromes or conditions that can induce skeletal muscle atrophy are congestive heart disease and some diseases of the liver.

Neuromuscular diseases are those that affect the muscles and/or their nervous control. In general, problems with nervous control can cause spasticity or paralysis, depending on the location and nature of the problem. A large proportion of neurological disorders, ranging from cerebrovascular accident (stroke) and Parkinson's disease to CreutzfeldtJakob disease, can lead to problems with movement or motor coordination.

Symptoms of muscle diseases may include weakness, spasticity, myoclonus and myalgia. Diagnostic procedures that may reveal muscular disorders include testing creatine kinase levels in the blood and electromyography (measuring electrical activity in muscles). In some cases, muscle biopsy may be done to identify a myopathy, as well as genetic testing to identify DNA abnormalities associated with specific myopathies and dystrophies.

A non-invasive elastography technique that measures muscle noise is undergoing experimentation to provide a way of monitoring neuromuscular disease. The sound produced by a muscle comes from the shortening of actomyosin filaments along the axis of the muscle. During contraction, the muscle shortens along its longitudinal axis and expands across the transverse axis, producing vibrations at the surface.[25]

The evolutionary origin of muscle cells in metazoans is a highly debated topic. In one line of thought scientists have believed that muscle cells evolved once and thus all animals with muscles cells have a single common ancestor. In the other line of thought, scientists believe muscles cells evolved more than once and any morphological or structural similarities are due to convergent evolution and genes that predate the evolution of muscle and even the mesoderm - the germ layer from which many scientists believe true muscle cells derive.

Schmid and Seipel argue that the origin of muscle cells is a monophyletic trait that occurred concurrently with the development of the digestive and nervous systems of all animals and that this origin can be traced to a single metazoan ancestor in which muscle cells are present. They argue that molecular and morphological similarities between the muscles cells in cnidaria and ctenophora are similar enough to those of bilaterians that there would be one ancestor in metazoans from which muscle cells derive. In this case, Schmid and Seipel argue that the last common ancestor of bilateria, ctenophora, and cnidaria was a triploblast or an organism with three germ layers and that diploblasty, meaning an organism with two germ layers, evolved secondarily due to their observation of the lack of mesoderm or muscle found in most cnidarians and ctenophores. By comparing the morphology of cnidarians and ctenophores to bilaterians, Schmid and Seipel were able to conclude that there were myoblast-like structures in the tentacles and gut of some species of cnidarians and in the tentacles of ctenophores. Since this is a structure unique to muscle cells, these scientists determined based on the data collected by their peers that this is a marker for striated muscles similar to that observed in bilaterians. The authors also remark that the muscle cells found in cnidarians and ctenophores are often contests due to the origin of these muscle cells being the ectoderm rather than the mesoderm or mesendoderm. The origin of true muscles cells is argued by others to be the endoderm portion of the mesoderm and the endoderm. However, Schmid and Seipel counter this skepticism about whether or not the muscle cells found in ctenophores and cnidarians are true muscle cells by considering that cnidarians develop through a medusa stage and polyp stage. They observe that in the hydrozoan medusa stage there is a layer of cells that separate from the distal side of the ectoderm to form the striated muscle cells in a way that seems similar to that of the mesoderm and call this third separated layer of cells the ectocodon. They also argue that not all muscle cells are derived from the mesendoderm in bilaterians with key examples being that in both the eye muscles of vertebrates and the muscles of spiralians these cells derive from the ectodermal mesoderm rather than the endodermal mesoderm. Furthermore, Schmid and Seipel argue that since myogenesis does occur in cnidarians with the help of molecular regulatory elements found in the specification of muscles cells in bilaterians that there is evidence for a single origin for striated muscle.[26]

In contrast to this argument for a single origin of muscle cells, Steinmetz et al. argue that molecular markers such as the myosin II protein used to determine this single origin of striated muscle actually predate the formation of muscle cells. This author uses an example of the contractile elements present in the porifera or sponges that do truly lack this striated muscle containing this protein. Furthermore, Steinmetz et al. present evidence for a polyphyletic origin of striated muscle cell development through their analysis of morphological and molecular markers that are present in bilaterians and absent in cnidarians, ctenophores, and bilaterians. Steimetz et al. showed that the traditional morphological and regulatory markers such as actin, the ability to couple myosin side chains phosphorylation to higher concentrations of the positive concentrations of calcium, and other MyHC elements are present in all metazoans not just the organisms that have been shown to have muscle cells. Thus, the usage of any of these structural or regulatory elements in determining whether or not the muscle cells of the cnidarians and ctenophores are similar enough to the muscle cells of the bilaterians to confirm a single lineage is questionable according to Steinmetz et al. Furthermore, Steinmetz et al. explain that the orthologues of the MyHc genes that have been used to hypothesize the origin of striated muscle occurred through a gene duplication event that predates the first true muscle cells (meaning striated muscle), and they show that the MyHc genes are present in the sponges that have contractile elements but no true muscle cells. Furthermore, Steinmetz et all showed that the localization of this duplicated set of genes that serve both the function of facilitating the formation of striated muscle genes and cell regulation and movement genes were already separated into striated myhc and non-muscle myhc. This separation of the duplicated set of genes is shown through the localization of the striated myhc to the contractile vacuole in sponges while the non-muscle myhc was more diffusely expressed during developmental cell shape and change. Steinmetz et al. found a similar pattern of localization in cnidarians with except with the cnidarian N. vectensis having this striated muscle marker present in the smooth muscle of the digestive track. Thus, Steinmetz et al. argue that the pleisiomorphic trait of the separated orthologues of myhc cannot be used to determine the monophylogeny of muscle, and additionally argue that the presence of a striated muscle marker in the smooth muscle of this cnidarian shows a fundamentally different mechanism of muscle cell development and structure in cnidarians.[27]

Steinmetz et al. continue to argue for multiple origins of striated muscle in the metazoans by explaining that a key set of genes used to form the troponin complex for muscle regulation and formation in bilaterians is missing from the cnidarians and ctenophores, and of 47 structural and regulatory proteins observed, Steinmetz et al. were not able to find even on unique striated muscle cell protein that was expressed in both cnidarians and bilaterians. Furthermore, the Z-disc seemed to have evolved differently even within bilaterians and there is a great deal diversity of proteins developed even between this clade, showing a large degree of radiation for muscle cells. Through this divergence of the Z-disc, Steimetz et al. argue that there are only four common protein components that were present in all bilaterians muscle ancestors and that of these for necessary Z-disc components only an actin protein that they have already argued is an uninformative marker through its pleisiomorphic state is present in cnidarians. Through further molecular marker testing, Steinmetz et al. observe that non-bilaterians lack many regulatory and structural components necessary for bilaterians muscle formation and do not find any unique set of proteins to both bilaterians and cnidarians and ctenophores that are not present in earlier, more primitive animals such as the sponges and amoebozoans. Through this analysis the authors conclude that due to the lack of elements that bilaterians muscles are dependent on for structure and usage, nonbilaterian muscles must be of a different origin with a different set regulatory and structural proteins.[27]

In another take on the argument, Andrikou and Arnone use the newly available data on gene regulatory networks to look at how the hierarchy of genes and morphogens and other mechanism of tissue specification diverge and are similar among early deuterostomes and protostomes. By understanding not only what genes are present in all bilaterians but also the time and place of deployment of these genes, Andrikou and Arnone discuss a deeper understanding of the evolution of myogenesis.[28]

In their paper Andrikou and Arnone argue that to truly understand the evolution of muscle cells the function of transcriptional regulators must be understood in the context of other external and internal interactions. Through their analysis, Andrikou and Arnone found that there were conserved orthologues of the gene regulatory network in both invertebrate bilaterians and in cnidarians. They argue that having this common, general regulatory circuit allowed for a high degree of divergence from a single well functioning network. Andrikou and Arnone found that the orthologues of genes found in vertebrates had been changed through different types of structural mutations in the invertebrate deuterostomes and protostomes, and they argue that these structural changes in the genes allowed for a large divergence of muscle function and muscle formation in these species. Andrikou and Arnone were able to recognize not only any difference due to mutation in the genes found in vertebrates and invertebrates but also the integration of species specific genes that could also cause divergence from the original gene regulatory network function. Thus, although a common muscle patterning system has been determined, they argue that this could be due to a more ancestral gene regulatory network being coopted several times across lineages with additional genes and mutations causing very divergent development of muscles. Thus it seems that myogenic patterning framework may be an ancestral trait. However, Andrikou and Arnone explain that the basic muscle patterning structure must also be considered in combination with the cis regulatory elements present at different times during development. In contrast with the high level of gene family apparatuses structure, Andrikou and Arnone found that the cis regulatory elements were not well conserved both in time and place in the network which could show a large degree of divergence in the formation of muscle cells. Through this analysis, it seems that the myogenic GRN is an ancestral GRN with actual changes in myogenic function and structure possibly being linked to later coopts of genes at different times and places.[28]

Evolutionarily, specialized forms of skeletal and cardiac muscles predated the divergence of the vertebrate/arthropod evolutionary line.[29][dead link] This indicates that these types of muscle developed in a common ancestor sometime before 700 million years ago (mya). Vertebrate smooth muscle was found to have evolved independently from the skeletal and cardiac muscle types.

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