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Cardiac stem cells in the post-Anversa era | European …

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At the turn of the century, prevailing dogma stated that the adult mammalian heart was incapable of self-repair. Postnatal growth reflected increases in cardiomyocyte size alone rather than through increases in cell number. This dogma was shaken by the demonstration that bone marrow cells could be used to regenerate heart muscle. The subsequent discovery that adult hearts contained cells that expressed the haematological stem cell marker c-Kit led to a large body of literature, mostly from Piero Aversas laboratory, which advanced the premise that cardiac c-Kit+ cells were clonogenic, multipotent, and capable of self-renewal (i.e. genuine heart stem cells). While this hypothesis was popularized and espoused by many, the validity of Anversas findings were questioned early on by several investigators who failed to reproduce key findings.1,2

On 14 October 2018, the Harvard Medical School and Brigham and Womens Hospital brought an end to this chapter as 31 papers from the lab pioneering heart c-Kit+ cells were recommended for retraction because the validity of the scientific data was uncertain. While the full identity of the papers affected is still unknown, the New England Journal of Medicine promptly issued an expression of concern that the data presented in two (heretofore) landmark papers in cardiac regeneration may not be reliable3 and outright retracted a 2011 paper demonstrating evidence for human lung c-Kit+ stem cells.4

On the heels of multiple corrections,511 institutional settlements,12 lawsuits,13 and prior retractions,14 it appears much of the literature supporting resident (in situ) c-Kit+ cells having any role in cardiac repair is open to question. The impact of this verdict is only now starting to be understood and has led many to question the concept of heart stem cells in the post-Anversa era.

Yes. Archaeological carbon-14 dating conclusively established that half of all cardiomyocytes are renewed over an individual lifespan.15 This repopulation decreases with advanced years. For example, at 25years old almost 1% of cardiomyocytes turn-over every year compared with only 0.5% turnover after 75years. Such numberslow but definitely not zerohave been confirmed by others using complementary methods in experimental animals.16,17

No. Reports began to emerge 10years ago questioning the cardiomyogenic potential of c-Kit+ cells.1820 Recent lineage tracking from multiple labs using complimentary techniques has established that endogenous cardiac c-Kit+ cells do not generate cardiomyocytes.2123

Probably not. Early reports panned through tissue lysate and heart sections for cells expressing embryonic or haematological stem markers in hopes of identifying cells that could be enticed to express cardiac markers in culture. In the absence of lineage tracking, the origin of the cells discovered is uncertain and very well may represent extra-cardiac contamination. It follows that cardio myogenesis seen before or after injury likely arises from myocardial de-differentiation only.24 Although cardiosphere-derived cells (CDCs) are clonogenic and multipotent in vitro,25 they have long been recognized not to function as cardiac progenitors after transplantation in vivo.26

In 2004, Messina et al. demonstrated a mixed population of CD105+ CD45-cells, explant-derived cells that spontaneously emigrate from heart tissue plated in culture.27 Forensic analysis showed these cells are intrinsically cardiac with no detectable seeding from extra-cardiac organs.28 To enable cell expansion to clinical doses, explant-derived cells have been antigenically selected or sphere cultured to generate c-Kit+ cells or CDCs, respectively (see Figure1). Independent labs have shown that both c-Kit+ cells (6 labs) or CDCs (45+ labs) improve heart function when delivered after injury. Unfortunately, studies providing direct comparisons between either cell type are often difficult to interpret as divergent cell culture methods or patient comorbidities influence cell potency; however, within CDCs, the small c-Kit+ cell fraction does not contribute to and is not necessary for, the observed gains in function.29

Figure 1

Schematic outline of heart-derived cell therapeutic manufacturing and identity. Explant-derived cells are cultured from myocardial tissue for antigenic selection (c-Kit+ cells, left panels) or sphere culture (CDCs, right panels) prior to expansion. Representative c-Kit+ cell images demonstrate freshly isolated human c-Kit+ cells (left panel, black dots, beads from magnetic-activated cell sorting) and during cell expansion (right panel, low confluence to highlight cell morphology). Representative images of CDCs cultured from transgenic mouse tissue expressing the c-Kit reporter (green fluorescent protein)18 highlighting the proportion of c-Kit+ cells within. Also shown is flow cytometry characterization from the SCIPIO (c-Kit+ cell trial, left panel)35 and CADUCEUS (CDC trial, right panel)41 trials contrasting the antigenic identity of each heart-derived cell therapeutic used in clinical trials.

Figure 1

Schematic outline of heart-derived cell therapeutic manufacturing and identity. Explant-derived cells are cultured from myocardial tissue for antigenic selection (c-Kit+ cells, left panels) or sphere culture (CDCs, right panels) prior to expansion. Representative c-Kit+ cell images demonstrate freshly isolated human c-Kit+ cells (left panel, black dots, beads from magnetic-activated cell sorting) and during cell expansion (right panel, low confluence to highlight cell morphology). Representative images of CDCs cultured from transgenic mouse tissue expressing the c-Kit reporter (green fluorescent protein)18 highlighting the proportion of c-Kit+ cells within. Also shown is flow cytometry characterization from the SCIPIO (c-Kit+ cell trial, left panel)35 and CADUCEUS (CDC trial, right panel)41 trials contrasting the antigenic identity of each heart-derived cell therapeutic used in clinical trials.

Not as much as we thought! Ex vivo expanded c-Kit+ cells were inspired by the Anversa literature and it was thought, until recently, that robust cell numbers persisted for many years after intramyocardial injection.30 The in situ c-Kit+ cell findings, which largely emanated from the well-funded Anversa lab, were directly extended to ex vivo expanded c-Kit+ cells. Since then, it has been concretely established that few transplanted cells engraft beyond a few days.31 This surprising observation revealed that c-Kit+ cells were evanescent, and thus not functioning as stem cells.

This realization came very late for c-Kit+ cells, unlike CDCs, which have been known for >10years to be effective despite little persistence of injected cells beyond 4weeks (i.e. 23% of the initial injectate).32,33 Fortunately, the CDC literature provides a clear template for these investigations with several articles listing comprehensive proteomic analysis, cytokine over-expression/subtraction data supporting causation, exosome profiling data and microRNA addition/subtraction data supporting a causative role in post infarct repair.34

Although very late in the game, a great deal of the basic phenotyping work is not yet known about c-Kit+ cells; including the fundamental differences between heart-derived and extra-cardiac c-Kit+ cells. It may be that c-Kit+ cells stimulate many of the immunomodulatory (macrophage polarization) and trophic (angiogenic, anti-apoptotic, mitotic and anti-scarring) endogenous repair mechanisms already identified in the CDC literature but much waits to be uncovered.

Reports of their death have been greatly exaggerated. The 2011 Phase 1 SCIPIO Trial demonstrated intra-coronary injection of c-Kit+ cells was safe and provided encouraging hints of efficacy as shown by increases in cardiac ejection fraction, New York Heart Association (NYHA) class and viable myocardium.35 But the subsequent 2014 expression of concern by The Lancet36 reflected cell product characterization, identity and manufacturing which were both done in Boston by Dr Anversas team.37 The impact of recent events on interpretation of the SCIPIO Trial is still not known but may emerge as the journals affected by the list of articles recommended for retraction receive more information.

The CONCERT HF Trial ( Identifier: NCT02501811) began in 2015 to explore the effects of combining heart-derived c-Kit+ cells with blood mesenchymal stem cells on post infarct repair.38 This trial was based upon two preclinical studies suggesting combined therapy increases transplanted cell engraftment to enhance cell treatment outcomes.39,40 With the Harvard c-Kit+ cell retractions, the NIHBLI paused the trial on 29 October 2018 to provide the Data and Safety Monitoring Board (DSMB) an opportunity to review the literature supporting the scientific foundations of the trial. Given the invasive nature of the trial (and the observation that a patient died during endomyocardial biopsy), this caution is appreciated to ensure that sufficient pre-clinical insight and clinical equipoise still exist in the new post-Anversa era.

At best, the future of heart c-Kit+ cells is uncertain. With the astounding number of key publications likely to be retracted, it may very well be that adult c-Kit+ cells are not fundamentally different enough from other heart-derived cells to warrant efforts exploring clinical efficacy beyond the multiple clinical trials completed or underway using CDCs or the CDC secretome.

Conflict of interest: none declared.

References are available as supplementary material at European Heart Journal online.

Published by Oxford University Press on behalf of the European Society of Cardiology 2019.

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Bone Marrow Stem Cells Stall Out in Chronic Lymphocytic …

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Snow and ice cause cars to stall out on the road to their destination. In patients with CLL, its their stem cells that stall out and researchers want to know why.

For patients who have chronic lymphocytic leukemia, fighting off a serious infection can be difficult and often is just not possible. And a team of Mayo researchers is starting to find out why in a paper published recently in the journal Leukemia.

What is Chronic Lymphocytic Leukemia?

This disease is cancer of an immune cell called a B lymphocyte. These cells form in bone marrow and migrate out to patrol in the blood stream and lymphoid organs. But in chronic lymphocytic leukemia, the immune system is depleted, a state called immunodeficiency. Because of that, people with this type of leukemia are prone to serious infections and the diseases those may cause. They are also prone to developing other types of cancer.

And its those resulting problems that may ultimately contribute to death explains Kay Medina, Ph.D., a Mayo Clinic immunologist. Dr. Medina specializes in how immune cells develop from bone marrow stem cells.

In our bone marrow, stem cells convert to red blood cells, platelets or a variety of immune cells. Those are then sent into the blood stream where they do their job. Red blood cells replace cells that are worn out.

White blood cells patrol the byways of our circulation, chasing down everything from cellular debris to bacteria to virus particles.But not in patients with chronic lymphocytic leukemia.

Joining the Team

Research on chronic lymphocytic leukemia is going on in several labs at Mayo Clinic. Dr. Medina got involved after speaking with colleagues Wei Ding, M.B.B.S, Ph.D., and Neil Kay, M.D., both chronic lymphocytic leukemia physician researchers.

Mayo has a strong tradition of encouraging physician/basic research collaborations to advance knowledge of disease mechanisms, development, and assessment of new treatment approaches, says Dr. Medina.

The basic research helps us understand the cause of the disease, in this case the leukemia cell, but it also helps to understand what the disease does to other parts of the body, such as the lymph nodes, spleen, blood and bone marrow, she says.

Bone marrow is the organ that replenishes all cells in the immune system but has not been evaluated for functional proficiency in CLL patients, explains Dr. Medina.

Checking out the Cells and their Environment

Kay Medina, Ph.D.

Dr. Medinas team, with funding from Mayo Clinics Center for Biomedical Discovery, decided to look at bone marrow stem cells and their ability to generate all blood cell types. Some of the immune deficiency may be the result of treatment, but untreated patients have the same problem. The chronic nature of the disease itself may also dampen immune activity. But Dr. Medina explains that the leukemia cells may promote an environment that suppresses immune function.

Our research seeks to add to the discussion by identifying additional ways patients with CLL are unable to fight off tumors and other diseases, says Dr. Medina.

In a paper published late last year, Dr. Medina and her team, including first author Bryce Manso who is a student in the Mayo Clinic Graduate School of Biomedical Sciences, examined bone marrow and blood samples from chronic lymphocytic leukemia patients and healthy controls to determine the frequency of bone marrow stem cells in each sample and how well they did their job.

Bryce Manso, presenting a poster to a conference attendee.

The authors reported that, in general, samples from patients with chronic lymphocytic leukemia have fewer stem cells in their bone marrow, and those stem cells that remain work less well than stem cells from controls.

Stalled-Out Bone Marrow Stem Cells

As to why this happens, the authors found that it was linked to loosening controls for the on/off switches which regulate this process, proteins called transcription factors. These proteins regulate key functions in the cell, and are out of whack in samples from chronic lymphocytic leukemia patients. They may prevent bone marrow stem cells from pursuing a pathway for development; stalling-out their ability to differentiate, resulting in decreased production of important blood cells that provide the first line of defense against infectious agents.

But, Dr. Medina cautions, there is more to this story.

This is an emerging area of research in that its both a unique explanation for the clinical problem of immune deficiency and it has been minimally studied, says Dr. Medina. Future studies are planned to look at specific transcription factors that control stem cell differentiation as well as how the presence of leukemic cells in the bone marrow alter blood cell development. They will then relate this information to clinically relevant complications reported in chronic lymphocytic leukemia patients, she says.

Basic Research to Improve Patient Care

Dr. Medina, her team, and their clinical colleagues hope that by understanding how bone marrow function is impaired in chronic lymphocytic leukemia patients, they can develop unique strategies to boost bone marrow function or find alternate treatments that do not block or modify marrow function.

Through this work we hope to find ways to reduce infections and the incidence of second cancers in chronic lymphocytic leukemia patients. Our research has the potential to improve quality of life as well as extend the lives of these patients says Dr. Medina.


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Tags: basic science, blood cancer, cancer, Center for Biomedical Discovery, chronic lymphocytic leukemia, Findings, immunology, Kay Medina, leukemia, Mayo Clinic Cancer Center, Neil Kay, News, Progress Updates, Wei Ding

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Bone Marrow Stem Cells | NSI Stem Cell

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Stem cell therapies have come a long way since the 1970s and 1980s. Today the ethical issues of harvesting stem cells have long been resolved through the discovery of several sources of potent stem cell types. Common sources include in the umbilical cord and placenta (post birth), bone marrow, and the fatty layer that lies just beneath everyones skin (adipose fat tissue). Of these resources, by far the most commonly accessed in the United States are adipose fat and bone marrow stem cells.The National Stem Cell Institute (NSI), a leading stem cell clinic in the U.S., has seen the development of these living resources usher in an exciting new age known as regenerative medicine. Because of their potency and new technologies that allow ease of access, stem cells are changing the very face of medicine. In particular, the harvesting of bone marrow stem cells has developed into a procedure that is minimally invasive, far more comfortable than bone marrow harvesting of the past, and able to be complete in just a few hours.Some Basics About Bone Marrow Stem CellsBone marrow is the living tissue found in the center of our bones. Marrow is a soft, sponge-like tissue. There are two types of bone marrow: red marrow and yellow marrow. In adults, red marrow is found mainly in the central skeleton, such as the pelvis, sternum, cranium, ribs, vertebrae, and scapulae. But it is also found in the ends of long bones such as in the arms and legs.When it comes to bone marrow stem cells, red marrow is what its all about. Red marrow holds an abundance of them. Stem cells are a kind of protocell that has not yet been assigned an exact physical or neurological function. You can think of them as microscopic packets of potential that stay on high alert for signals telling them where they are needed and what type of cell they need to become.Bone marrow stem cells are multipotent, which means they have the ability to become virtually any type of tissue cell, including:

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Stem Cell Therapy for Neuropathy: What Can We Expect …

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As the body ages, its only natural that some of its processes should break down. Humans become clumsier, stiffer, their reaction times slower, their senses duller. This is often due to the fact that nerves in the extremities grow less sensitive over time, transmitting messages to the brain more slowly and feeling less acutely a condition known as peripheral neuropathy or simply neuropathy.

While some of that is normal, especially in the golden years, neuropathy often manifests in people much too young in their 30s, 40s, or 50s as a result of a disease such as diabetes or autoimmune issues. Unfortunately, the condition can significantly hamper a persons quality of life, making mobility difficult and limiting everyday activities.

The good news? Neuropathy may have a cure, or at least a solid treatment, on the horizon. Stem cells show great promise for a wide variety of conditions, and nerve damage is the latest of these. To see how it can help, its important to understand what stem cell treatment is, what neuropathy is and what causes it, and how the former can address the latter.

In this article:

The body is made of trillions of tissue-specific cells, making up organs, skin, muscle, bone, nerves, and all other tissue. Some of these can renew indefinitely, such as blood cells. Others, however, cannot replace themselves: Once they have divided a certain number of times or become damaged, theyre dead for good. That goes for nerves and brain tissue, for example.

There is, however, an answer. The developing embryo uses stem cells, or master cells capable of differentiating into any kind of tissue in the human body, to transform one fertilized egg into a fully functional baby human. While adult humans lack these pluripotent stem cells that can transform into anything, they do have multipotent stem cells, which are tissue-specific master cells (such as blood cells).

By harvesting these multipotent stem cells from blood or fat tissue, scientists can induce the cells to become pluripotent, meaning theyre now capable of becomingany tissue in the human body. Essentially, researchers have figured out how to reverse-engineer adult stem cells to become all-powerful embryonic cells. This meansstem cells have a huge range of possible uses.

In other cases, multipotent stem cells alone are enough to heal some parts of the human bodysuch as nerves.

Peripheral neuropathymanifests in a number of ways. It causes pain, weakness, and tingling in affected areas, making it hard to lift objects, grasp items, walk competently, and more. Typically it affects the hands and feet most strongly, though it can also cause symptoms in the arms, legs, and face. Not only does it affect motor coordination,but it also makes it hard for the body to sense the environment, including temperature, pain, vibration, and touch.

A more serious manifestation of the disease is autonomic neuropathy, which influences more than the periphery of the body. It also messes with blood pressure, bladder and bowel function, digestion, sweating, and heart rate. Polyneuropathy is when the condition starts at the periphery of the body but gradually spreads inward.

Diabetic neuropathy is the most well-known incarnation of this disease. It is a result of high glucose and fat levels in the blood, which can damage nerves.Other causes include:

If the bad news is there are so many potential causes of neuropathy, the good news is stem cell treatments have the potential to address all of them.

In the case of neuropathy, stem cell treatment is simpler than in other conditions. Mesenchymal stem cells (certain types of multipotent stem cells) releaseneuroprotective and neuroregenerative factors, so when they are injected into the bloodstream they can begin to rebuild nerves and undo the damage caused by the disease. Also, because these stem cells replicate indefinitely, they will offer these benefits for the rest of the patients life.

The basic process is that scientists harvest these cells from the patient (autologous transplant) or from a donor (allogeneic transplant), then cultivate them until they reach certain levels before reinjecting them back into the patient. The stem cells, with the help of hormones and growth factors, seek out and repair the damage done by neuropathy.

The main risks to stem cell treatment include reaction to the injection. In an autologous transplant, the patient may react to the preservatives and other chemicals used by way of necessity. In an allogeneic transplant, the patient may exhibit an immune response to donor cells, or vice versa with the donor cells seeing the patients body as an invader and attacking it. All of the above reactions can prove minor or, on the other end of the spectrum, fatal.

The severity of the problem will, therefore, dictate whether or not it is worth moving forward. Note that those whodochoose to pursue the treatment often have extremely good results.

Unlike some other stem cell treatments, which remain in preliminary stages, stem cell therapy for neuropathy has thus far received serious attention. However, thesmall sample size and difficult conditions of clinical trialsmake it hard to say yet whether this treatment will become widespread or receive FDA approval.Other studies have demonstrated more significant resultsin the treatment of facial pain and may pave the way for future neuropathy treatments using stem cells.

For now, those suffering from neuropathy should seek the advice of a physician. If there are clinical trials available nearby, thats the place to start. Its possible to seek stem cell therapy through a clinic as well as through a clinical study or research institution, but make sure to research the provider thoroughly. With stem cells becoming such a relevantapproach to medical conditions of all kinds, its not safe to conclude that all providers are equally experienced or effective.

If you found this blog valuable, subscribe to BioInformants stem cell industry updates.

As the first and only market research firm to specialize in the stem cell industry, BioInformant research is cited by The Wall Street Journal, Xconomy, AABB, and Vogue Magazine. Bringing you breaking news on an ongoing basis, we encourage you to join more than half a million loyal readers, including physicians, scientists, executives, and investors.

Did this article address your concerns about neuropathy? Let us know in the comments section below.

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Stem Cell Therapy for Neuropathy: What Can We Expect

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Blood and bone marrow stem cell donation – Mayo Clinic

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If you are planning to donate stem cells, you have agreed to allow doctors to draw bone marrow stem cells from either your blood or bone marrow for transplantation.

There are two broad types of stem cells: embryonic and bone marrow stem cells. Embryonic stem cells are studied in therapeutic cloning and other types of research. Bone marrow stem cells are formed and mature in the bone marrow and are then released into the bloodstream. This type of stem cell is used in the treatment of cancers.

In the past, surgery to draw bone marrow stem cells directly from the bone was the only way to collect stem cells. Today, however, it's more common to collect stem cells from the blood. This is called peripheral blood stem cell donation.

Stem cells can also be collected from umbilical cord blood at birth. However, only a small amount of blood can be retrieved from the umbilical cord, so this type of transplant is generally reserved for children and small adults.

Every year, thousands of people in the U.S. are diagnosed with life-threatening diseases, such as leukemia or lymphoma, for which a stem cell transplant is the best or the only treatment. Donated blood stem cells are needed for these transplants.

You might be considering donating blood or bone marrow because someone in your family needs a stem cell transplant and doctors think you might be a match for that person. Or perhaps you want to help someone else maybe even someone you don't know who's waiting for a stem cell transplant.

Bone marrow stem cells are collected from the posterior section of the pelvic bone under general anesthesia. The most serious risk associated with donating bone marrow involves the use and effects of anesthesia during surgery. After the surgery, you might feel tired or weak and have trouble walking for a few days. The area where the bone marrow was taken out might feel sore for a few days. You can take a pain reliever for the discomfort. You'll likely be able to get back to your normal routine within a couple of days, but it may take a couple of weeks before you feel fully recovered.

The risks of this type of stem cell donation are minimal. Before the donation, you'll get injections of a medicine that increases the number of stem cells in your blood. This medicine can cause side effects, such as bone pain, muscle aches, headache, fatigue, nausea and vomiting. These usually disappear within a couple of days after you stop the injections. You can take a pain reliever for the discomfort. If that doesn't help, your doctor can prescribe another pain medicine for you.

For the donation, you'll have a thin, plastic tube (catheter) placed in a vein in your arm. If the veins in your arms are too small or have thin walls, you may need to have a catheter put in a larger vein in your neck, chest or groin. This rarely causes side effects, but complications that can occur include air trapped between your lungs and your chest wall (pneumothorax), bleeding, and infection. During the donation, you might feel lightheaded or have chills, numbness or tingling around your mouth, and cramping in your hands. These will go away after the donation.

If you want to donate stem cells, you can talk to your doctor or contact the National Marrow Donor Program, a federally funded nonprofit organization that keeps a database of volunteers who are willing to donate.

If you decide to donate, the process and possible risks of donating will be explained to you. You will then be asked to sign a consent form. You can choose to sign or not. You won't be pressured to sign the form.

After you agree to be a donor, you'll have a test called human leukocyte antigen (HLA) typing. HLAs are proteins found in most cells in your body. This test helps match donors and recipients. A close match increases the chances that the transplant will be a success.

If you sign up with a donor registry, you may or may not be matched with someone who needs a blood stem cell transplant. However, if HLA typing shows that you're a match, you'll undergo additional tests to make sure you don't have any genetic or infectious diseases that can be passed to the transplant recipient. Your doctor will also ask about your health and your family history to make sure that donation will be safe for you.

A donor registry representative may ask you to make a financial contribution to cover the cost of screening and adding you to the registry, but this is usually voluntary. Because cells from younger donors have the best chance of success when transplanted, anyone between the ages of 18 and 44 can join the registry for free. People ages 45 to 60 are asked to pay a fee to join; age 60 is the upper limit for donors.

If you're identified as a match for someone who needs a transplant, the costs related to collecting stem cells for donation will be paid by that person or by his or her health insurance.

Collecting stem cells from bone marrow is a type of surgery and is done in the operating room. You'll be given an anesthetic for the procedure. Needles will be inserted through the skin and into the bone to draw the marrow out of the bone. This process usually takes one to two hours.

After the bone marrow is collected, you'll be taken to the recovery room while the anesthetic wears off. You may then be taken to a hospital room where the nursing staff can monitor you. When you're fully alert and able to eat and drink, you'll likely be released from the hospital.

If blood stem cells are going to be collected directly from your blood, you'll be given injections of a medication to stimulate the production of blood stem cells so that more of them are circulating in your bloodstream. The medication is usually started several days before you're going to donate.

During the donation, blood is usually taken out through a catheter in a vein in your arm. The blood is sent through a machine that takes out the stem cells. The rest of the blood is then returned to you through a vein in your other arm. This process is called apheresis. It takes two to six hours and is done as an outpatient procedure. You'll typically undergo two to four apheresis sessions, depending on how many blood stem cells are needed.

Recovery times vary depending on the individual and type of donation. But most blood stem cell donors are able to return to their usual activities within a few days to a week after donation.

Recovery times vary depending on the individual and type of donation. But most blood stem cell donors are able to return to their usual activities within a few days to a week after donation.

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this disease.

Dec. 20, 2018

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Whole Bone Marrow –

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Bone Marrow (BM) contains hematopoietic stem/progenitor cells, which have the potential to self-renew, proliferate, and differentiate into multi-lineage blood cells. Multipotent, non-hematopoietic stem cells, such as mesenchymal stem cells, can be isolated from human BM as well. These non-hematopoietic, mesenchymal stem cells are capable of both self-renewal and differentiation into bone, cartilage, muscle, tendons, and fat. BM is drawn into a 60cc syringe containing heparin (80 U/mL of BM) from the posterior iliac crest, 25 mL/site, from a maximum of four sites.CustomizationLet us know how we can customize your product today Custom InquiryDonor CriteriaAge18-65 years oldWeight>= 130 lbsScreened before donationHIV (HIV 1 & 2 Ab)HBV (Surface Antigen HbsAg)HCV (HCVAb)Donation FrequencyMinimum 10 weeks between donationsDonors with any of the following will be excluded from donatingPregnancyHistory of heart, lung, liver, or kidney diseaseHistory of asthmaBlood and bleeding disorders including sickle cell diseaseNeurologic disordersAutoimmune disordersCancerDiabetesOther CriteriaMust be in general good healthMust have accessible hipsComplete Blood Count lab test must meet protocol specsRequired to sign procedure-specific consent form

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What is CAR-T Cell Therapy | CAR-T Definition | Bioinformant

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About The Brain and Spinal Cord | Neurosurgery …

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Together, the brain and spinal cord form the central nervous system. This complex system is part of everything we do. It controls the things we choose to do -- like walk and talk -- and the things our body does automatically -- like breathe and digest food. The central nervous system is also involved with our senses -- seeing, hearing, touching, tasting, and smelling -- as well as our emotions, thoughts, and memory.

The brain is a soft, spongy mass of nerve cells and supportive tissue. It has three major parts: the cerebrum, the cerebellum, and the brain stem. The parts work together, but each has special functions.

The cerebrum, the largest part of the brain, fills most of the upper skull. It has two halves called the left and right cerebral hemispheres. The cerebrum uses information from our senses to tell us what's going on around us and tells our body how to respond. The right hemisphere controls the muscles on the left side of the body, and the left hemisphere controls the muscles on the right side of the body. This part of the brain also controls speech and emotions as well as reading, thinking, and learning.

The cerebellum, under the cerebrum at the back of the brain, controls balance and complex actions like walking and talking.

The brain stem connects the brain with the spinal cord. It controls hunger and thirst and some of the most basic body functions, such as body temperature, blood pressure, and breathing.

The brain is protected by the bones of the skull and by a covering of three thin membranes called meninges. The brain is also cushioned and protected by cerebrospinal fluid. This watery fluid is produced by special cells in the four hollow spaces in the brain, called ventricles. It flows through the ventricles and in spaces between the meninges. Cerebrospinal fluid also brings nutrients from the blood to the brain and removes waste products from the brain.

The spinal cord is made up of bundles of nerve fibers. It runs down from the brain through a canal in the center of the bones of the spine. These bones protect the spinal cord. Like the brain, the spinal cord is covered by the meninges and cushioned by cerebrospinal fluid.

Spinal nerves connect the brain with the nerves in most parts of the body. Other nerves go directly from the brain to the eyes, ears, and other parts of the head. This network of nerves carries messages back and forth between the brain and the rest of the body

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Bone Marrow Transplant | CureSearch

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Before the transplant admission:

When the healthcare team decides that BMT is the best treatment option for your child, they will schedule a lengthy conversation with you to explain the procedure. They will explain the many risks associated with BMT, as well as what you can expect before, during, and after the transplant.

Your child will undergo testing to make sure he/she is healthy enough to withstand the rigors of transplant. Testing will include evaluation of the heart function with electrocardiogram (ECG) and kidney and liver function, and infection status. Depending upon the disease, a bone marrow aspirate and spinal tap may be performed.

When your child is deemed healthy enough for BMT, physicians will usually insert a central line catheter that allows easy access to a large vein in the chest. The catheter will be used to deliver the new stem cells, as well as blood, antibiotics, and other medications during treatment.

Preparation Before Transplant:

Your child will be given preparative treatment, called conditioning before the transplant. Conditioning includes high doses of chemotherapy and sometimes, radiation of the whole body. The type and purpose of conditioning depends upon your childs underlying diagnosis but may include:

Commonly used drugs include:

The Transplant

Once conditioning is complete, stem cells are given through a catheter. This is very similar to a blood transfusion. After traveling through the bloodstream to the bone marrow, the transplanted stem cells will begin to make red and white blood cells, and platelets.

It can take between 14 and 30 days for enough blood cells, particularly white blood cells, to be created so the body can fight infection. The identification of new blood cells and an increase in white blood cells following BMT is called engraftment. Until then, your child will be at a high risk for infection, anemia, and bleeding. Your child will remain in the hospital until he or she is well enough for discharge.

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Bone marrow transplant | UF Health, University of Florida …

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A bone marrow transplant is a procedure to replace damaged or destroyed bone marrow with healthy bone marrow stem cells.

Bone marrow is the soft, fatty tissue inside your bones. The bone marrow produces blood cells. Stem cells are immature cells in the bone marrow that give rise to all of your different blood cells.

Transplant - bone marrow; Stem cell transplant; Hematopoietic stem cell transplant; Reduced intensity nonmyeloablative transplant; Mini transplant; Allogenic bone marrow transplant; Autologous bone marrow transplant; Umbilical cord blood transplant; Aplastic anemia - bone marrow transplant; Leukemia - bone marrow transplant; Lymphoma - bone marrow transplant; Multiple myeloma - bone marrow transplant

Before the transplant, chemotherapy, radiation, or both may be given. This may be done in 2 ways:

There are three kinds of bone marrow transplants:

A stem cell transplant is usually done after chemotherapy and radiation is complete. The stem cells are delivered into your bloodstream usually through a tube called a central venous catheter. The process is similar to getting a blood transfusion. The stem cells travel through the blood into the bone marrow. Most times, no surgery is needed.

Donor stem cells can be collected in two ways:

A bone marrow transplant replaces bone marrow that is either not working properly or has been destroyed (ablated) by chemotherapy or radiation. Doctors believe that for many cancers, the donor's white blood cells may attack any remaining cancer cells, similar to when white cells attack bacteria or viruses when fighting an infection.

Your health care provider may recommend a bone marrow transplant if you have:

A bone marrow transplant may cause the following symptoms:

Possible complications of a bone marrow transplant depend on many things, including:

Complications may include:

Your provider will ask about your medical history and do a physical exam. You will have many tests before treatment begins.

Before transplant, you will have 1 or 2 tubes, called catheters, inserted into a blood vessel in your neck or arms. This tube allows you to receive treatments, fluids, and sometimes nutrition. It is also used to draw blood.

Your provider will likely discuss the emotional stress of having a bone marrow transplant. You may want to meet with a counselor. It is important to talk to your family and children to help them understand what to expect.

You will need to make plans to help you prepare for the procedure and handle tasks after your transplant:

A bone marrow transplant is usually done in a hospital or medical center that specializes in such treatment. Most of the time, you stay in a special bone marrow transplant unit in the center. This is to limit your chance of getting an infection.

Depending on the treatment and where it is done, all or part of an autologous or allogeneic transplant may be done as an outpatient. This means you do not have to stay in the hospital overnight.

How long you stay in the hospital depends on:

While you are in the hospital:

After you leave the hospital, be sure to follow instructions on how to care for yourself at home.

How well you do after the transplant depends on:

A bone marrow transplant may completely or partially cure your illness. If the transplant is a success, you can go back to most of your normal activities as soon as you feel well enough. Usually it takes up to 1 year to recover fully, depending on what complications occur.

Complications or failure of the bone marrow transplant can lead to death.

Bashir Q, Champlin R. Hematopoietic stem cell transplantation. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Abeloff's Clinical Oncology. 5th ed. Philadelphia, PA: Elsevier Saunders; 2014:chap 30.

Heslop HE. Overview and choice of donor of hematopoietic stem cell transplantation. In: Hoffman R, Benz EJ, Silberstein LE, et al, eds. Hematology: Basic Principles and Practice. 7th ed. Philadelphia, PA: Elsevier; 2018:chap 103.

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Glossary |

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Adult stem cell - See somatic stem cell.

Astrocyte - A type of supporting (glial) cell found in the nervous system.

Blastocoel - The fluid-filled cavity inside the blastocyst, an early, preimplantation stage of the developing embryo.

Blastocyst - Apreimplantationembryo consisting of a sphere made up of an outer layer of cells (thetrophoblast), a fluid-filled cavity (theblastocoel), and a cluster of cells on the interior (theinner cell mass).

Bone marrow stromal cells - A population of cells found in bone marrow that are different from blood cells.

Bone marrow stromal stem cells (skeletal stem cells) - A multipotent subset of bone marrow stromal cells able to form bone, cartilage, stromal cells that support blood formation, fat, and fibrous tissue.

Cell-based therapies - Treatment in which stem cells are induced to differentiate into the specific cell type required to repair damaged or destroyed cells or tissues.

Cell culture - Growth of cells in vitro in an artificial medium for research.

Cell division - Method by which a single cell divides to create two cells. There are two main types of cell division depending on what happens to the chromosomes: mitosis and meiosis.

Chromosome - A structure consisting of DNA and regulatory proteins found in the nucleus of the cell. The DNA in the nucleus is usually divided up among several chromosomes.The number of chromosomes in the nucleus varies depending on the species of the organism. Humans have 46 chromosomes.

Clone - (v) To generate identical copies of a region of a DNA molecule or to generate genetically identical copies of a cell, or organism; (n) The identical molecule, cell, or organism that results from the cloning process.

Cloning - See Clone.

Cord blood stem cells - See Umbilical cord blood stem cells.

Culture medium - The liquid that covers cells in a culture dish and contains nutrients to nourish and support the cells. Culture medium may also include growth factors added to produce desired changes in the cells.

Differentiation - The process whereby an unspecialized embryonic cell acquires the features of a specialized cell such as a heart, liver, or muscle cell. Differentiation is controlled by the interaction of a cell's genes with the physical and chemical conditions outside the cell, usually through signaling pathways involving proteins embedded in the cell surface.

Directed differentiation - The manipulation of stem cell culture conditions to induce differentiation into a particular cell type.

DNA - Deoxyribonucleic acid, a chemical found primarily in the nucleus of cells. DNA carries the instructions or blueprint for making all the structuresand materials the body needs to function. DNA consists of both genes and non-gene DNA in between the genes.

Ectoderm - The outermost germ layer of cells derived from the inner cell mass of the blastocyst; gives rise to the nervous system, sensory organs, skin, and related structures.

Embryo - In humans, the developing organism from the time of fertilization until the end of the eighth week of gestation, when it is called a fetus.

Embryoid bodies - Rounded collections of cells that arise when embryonic stem cells are cultured in suspension. Embryoid bodies contain cell types derived from all threegerm layers.

Embryonic germ cells - Pluripotent stem cells that are derived from early germ cells (those that would become sperm and eggs). Embryonic germ cells are thought to have properties similar to embryonic stem cells.

Embryonic stem cells - Primitive (undifferentiated) cells that are derived from preimplantation-stageembryos, are capable of dividing without differentiating for a prolonged period in culture, and are known to develop into cells and tissues of the three primary germ layers.

Embryonic stem cell line - Embryonic stem cells, which have been cultured under in vitro conditions that allow proliferation without differentiation for months to years.

Endoderm - The innermost layer of the cells derived from the inner cell mass of the blastocyst; it gives rise to lungs, other respiratory structures, and digestive organs, or generally "the gut."

Enucleated - Having had its nucleus removed.

Epigenetic - The process by which regulatory proteins can turn genes on or off in a way that can be passed on during cell division.

Feeder layer - Cells used in co-culture to maintain pluripotent stem cells. For human embryonic stem cell culture, typical feeder layers include mouse embryonic fibroblasts (MEFs) or human embryonic fibroblasts that have been treated to prevent them from dividing.

Fertilization - The joining of the male gamete (sperm) and the female gamete (egg).

Fetus - In humans, the developing human from approximately eight weeks after conception until the time of its birth.

Gamete - An egg (in the female) or sperm (in the male) cell. See also Somatic cell.

Gastrulation - The process in which cells proliferate and migrate within the embryo to transform the inner cell mass of the blastocyst stage into an embryo containing all three primary germ layers.

Gene - A functional unit of heredity that is a segment of DNA found on chromosomes in the nucleus of a cell. Genes direct the formation of an enzyme or other protein.

Germ layers - After the blastocyst stage of embryonic development, the inner cell mass of the blastocyst goes through gastrulation, a period when the inner cell mass becomes organized into three distinct cell layers, called germ layers. The three layers are the ectoderm, the mesoderm, and the endoderm.

Hematopoietic stem cell - A stem cell that gives rise to all red and white blood cells and platelets.

Human embryonic stem cell (hESC) - A type of pluripotent stem cell derived from early stage human embryos, up to and including the blastocyststage. hESCs are capable of dividing without differentiating for a prolonged period in culture and are known to develop into cells and tissues of the three primary germ layers.

Induced pluripotent stem cell (iPSC) - A type of pluripotent stem cell, similar to an embryonic stem cell, formed by the introduction of certain embryonic genes into a somatic cell.

In vitro - Latin for "in glass;" in a laboratory dish or test tube; an artificial environment.

In vitro fertilization - A technique that unites the egg and sperm in a laboratory instead of inside the female body.

Inner cell mass (ICM) - The cluster of cells inside the blastocyst. These cells give rise to the embryo and ultimately the fetus. The ICM may be used to generate embryonic stem cells.

Long-term self-renewal - The ability of stem cells to replicate themselves by dividing into the same non-specialized cell type over long periods (many months to years) depending on the specific type of stem cell.

Meiosis - The type of cell division a diploid germ cell undergoes to produce gametes (sperm or eggs) that will carry half the normal chromosome number. This is to ensure that when fertilization occurs, the fertilized egg will carry the normal number of chromosomes rather than causing aneuploidy (an abnormal number of chromosomes).

Mesenchymal stem cells - A term that is currently used to define non-blood adult stem cells from a variety of tissues, although it is not clear that mesenchymal stem cells from different tissues are the same.

Mesoderm - Middle layer of a group of cells derived from the inner cell mass of the blastocyst; it gives rise to bone, muscle, connective tissue, kidneys, and related structures.

Microenvironment - The molecules and compounds such as nutrients and growth factors in the fluid surrounding a cell in an organism or in the laboratory, which play an important role in determining the characteristics of the cell.

Mitosis - The type of cell division that allows a population of cells to increase its numbers or to maintain its numbers. The number of chromosomes in each daughter cell remains the same in this type of cell division.

Multipotent - Having the ability to develop into more than one cell type of the body. See also pluripotent and totipotent.

Neural stem cell - A stem cell found in adult neural tissue that can give rise to neurons and glial (supporting) cells. Examples of glial cells include astrocytes and oligodendrocytes.

Neurons - Nerve cells, the principal functional units of the nervous system. A neuron consists of a cell body and its processes - an axon and one or more dendrites. Neurons transmit information to other neurons or cells by releasing neurotransmitters at synapses.

Oligodendrocyte - A supporting cell that provides insulation to nerve cells by forming a myelin sheath (a fatty layer) around axons.

Parthenogenesis - The artificial activation of an egg in the absence of a sperm; the egg begins to divide as if it has been fertilized.

Passage - In cell culture, the process in which cells are disassociated, washed, and seeded into new culture vessels after a round of cell growth and proliferation. The number of passages a line of cultured cells has gone through is an indication of its age and expected stability.

Pluripotent - The state of a single cell that is capable of differentiating into all tissues of an organism, but not alone capable of sustaining full organismal development.

Scientists demonstrate pluripotency by providing evidence of stable developmental potential, even after prolonged culture, to form derivatives of all three embryonic germ layers from the progeny of a single cell and to generate a teratoma after injection into an immunosuppressed mouse.

Polar body - A polar body is a structure produced when an early egg cell, or oogonium, undergoes meiosis. In the first meiosis, the oogonium divides its chromosomes evenly between the two cells but divides its cytoplasm unequally. One cell retains most of the cytoplasm, while the other gets almost none, leaving it very small. This smaller cell is called the first polar body. The first polar body usually degenerates. The ovum, or larger cell, then divides again, producing a second polar body with half the amount of chromosomes but almost no cytoplasm. The second polar body splits off and remains adjacent to the large cell, or oocyte, until it (the second polar body) degenerates. Only one large functional oocyte, or egg, is produced at the end of meiosis.

Preimplantation - With regard to an embryo, preimplantation means that the embryo has not yet implanted in the wall of the uterus. Human embryonic stem cells are derived from preimplantation-stage embryos fertilized outside a woman's body (in vitro).

Proliferation - Expansion of the number of cells by the continuous division of single cells into two identical daughter cells.

Regenerative medicine - A field of medicine devoted to treatments in which stem cells are induced to differentiate into the specific cell type required to repair damaged or destroyed cell populations or tissues. (See also cell-based therapies).

Reproductive cloning - The process of using somatic cell nuclear transfer (SCNT) to produce a normal, full grown organism (e.g., animal) genetically identical to the organism (animal) that donated the somatic cell nucleus. In mammals, this would require implanting the resulting embryo in a uterus where it would undergo normal development to become a live independent being. The firstmammal to be created by reproductive cloning was Dolly the sheep, born at the Roslin Institute in Scotland in 1996. See also Somatic cell nuclear transfer (SCNT).

Signals - Internal and external factors that control changes in cell structure and function. They can be chemical or physical in nature.

Somatic cell - Any body cell other than gametes (egg or sperm); sometimes referred to as "adult" cells. See also Gamete.

Somatic cell nuclear transfer (SCNT) - A technique that combines an enucleated egg and the nucleus of a somatic cell to make an embryo. SCNT can be used for therapeutic or reproductive purposes, but the initial stage that combines an enucleated egg and a somatic cell nucleus is the same. See also therapeutic cloning and reproductive cloning.

Somatic (adult) stem cell - A relatively rare undifferentiated cell found in many organs and differentiated tissues with a limited capacity for both self renewal (in the laboratory) and differentiation. Such cells vary in their differentiation capacity, but it is usually limited to cell types in the organ of origin. This is an active area of investigation.

Stem cells - Cells with the ability to divide for indefinite periods in culture and to give rise to specialized cells.

Stromal cells - Connective tissue cells found in virtually every organ. In bone marrow, stromal cells support blood formation.

Subculturing - Transferring cultured cells, with or without dilution, from one culture vessel to another.

Surface markers - Proteins on the outside surface of a cell that are unique to certain cell types and that can be visualized using antibodies or other detection methods.

Teratoma - A multi-layered benign tumor that grows from pluripotent cells injected into mice with a dysfunctional immune system. Scientists test whether they have established a human embryonic stem cell (hESC) line by injecting putative stem cells into such mice and verifying that the resulting teratomas contain cells derived from all three embryonic germ layers.

Therapeutic cloning - The process of using somatic cell nuclear transfer (SCNT) to produce cells that exactly match a patient. By combining a patient's somatic cell nucleus and an enucleated egg, a scientist may harvest embryonic stem cells from the resulting embryo that can be used to generate tissues that match a patient's body. This means the tissues created are unlikely to be rejected by the patient's immune system. See also Somatic cell nuclear transfer (SCNT).

Totipotent - The state of a cell that is capable of giving rise to all types of differentiated cells found in an organism, as well as the supporting extra-embryonic structures of the placenta. A single totipotent cell could, by division in utero, reproduce the whole organism. (See also Pluripotent and Multipotent).

Transdifferentiation - The process by which stem cells from one tissue differentiate into cells of another tissue.

Trophoblast - The outer cell layer of the blastocyst. It is responsible for implantation and develops into the extraembryonic tissues, including the placenta, and controls the exchange of oxygen and metabolites between mother and embryo.

Umbilical cord blood stem cells - Stem cells collected from the umbilical cord at birth that can produce all of the blood cells in the body. Cord blood is currently used to treat patients who have undergone chemotherapy to destroy their bone marrow due to cancer or other blood-related disorders.

Undifferentiated - A cell that has not yet developed into a specialized cell type.

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Japan’s Laws Supporting Accelerated Pathways for Cell …

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In late 2014, Japan passed two new laws that revolutionizedthe commercialization ofcell therapies within the country by providing an accelerated pathway for product approvals. While there has been much discussion about these laws, few people have a clear understanding of the implications of these regulations on a global scale.

Below, we summarize the laws, identify their importance, and most importantly, speak to howJapan has become a gateway country for regenerative medicines.

New regulations accelerating the approval of regenerative therapeutics in Japan took effect November 25, 2014. The significance of these regulations is that they allow companies to receive conditional marketing approval and commercialize regenerative medicine products while clinical trials continue through the later stages.

The accelerated commercialization of cell therapies is part of the economic revitalization plan initiated by Prime Minister Shinz Abe. Under Shinz Abe, Japan has been pursuing regenerative medicine and cellular therapy as key strategies to the Japans economic growth. Japans Education Ministry also indicated that it is planning to spend 110 billion yen ($1.13 billion) on iPS cellresearch during the next 10 years, and the Japanese parliament has been discussing bills that would speed the approval process and ensure the safety of such treatments.[1]

In late 2014, Japan exercised the following acts:

The aim of the first act was to accelerate the clinical application and commercialization of innovative regenerative medicine therapies. It covers clinical research and medical practice using processed cells and specifies the procedure required for clearance to administer cell procedures to humans. These guidelines are very important to the use the cells within clinical stages.

The PMD Acts definition of regenerative medicine includes tissue-engineered products, cell therapy products, and gene therapy products.

The intent of the laws is to accelerate the commercialization of cell therapeutics within Japan by allowing companies to benefit from conditional marketing authorization.

Therefore, cell therapies that show safety and probable efficacy during Phase I and Phase II trials can get conditional approval for up to seven years, during which time:

1) Larger-scale, later-stage clinical trials are performed2) Revenue from the cell therapy is pursued within the Japanese market

During the seven-year conditional approval period, companies must continue to submit clinical trial data to Japans Pharmaceuticals and Medical Devices Agency (PMDA), and subsequentlyapply for final marketing approval or withdraw the product within seven years.

This safety data can then be used by non-Japanese participants, which is a massive benefit to foreign companies, such as those located in the United States. The regulatory environment in Japan provides companies with the unique opportunity to fast track a clinical trial and seek approval of a new cell therapy product within the Japanese market.

As Kaz Hirao, CEO of Cellular Dynamics International (CDI), shared with BioInformant:This has made Japan a gate country for developing innovative cell therapies with the potential to address major unmet medical needs. It has has provided a strategic opportunity to American companies, because they can benefit from fast track applications through doing clinical testing within Japan and subsequently developing its cell therapy across the rest of the world. Numerous American and Australian companies are pursuing this strategy, as well as other companies from other countries worldwide.[2]

Footnotes[1] Dvorak, K. (2014).Japan Makes Advance on Stem-Cell Therapy[Online]. Available at: Web. 8 Apr. 2015.[2]Interview with Kaz Hirao, CEO of Cellular Dynamics International (CDI), a FUJIFILM Company. Conducted by BioInformants President/CEO, Cade Hildreth [January 29, 2017]. Available at:

Japans Laws Supporting Accelerated Pathways for Cell Therapies

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Skin Program | Harvard Stem Cell Institute (HSCI)

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Scientists in the HSCI Skin Program are using stem cells to regenerate tissue without scarring.

Because scars are made of fibrous tissue, they can seriously impair the function of an organ. To investigate how stem cells function in regenerative wound healing, cancers, and skin aging, and how they malfunction in scarring and fibrosis, we explore the fundamental roles of skin stem cells in health and disease. The insights we gain help us explore the reprogramming of skin cells to repair any part of the body.

Our scientists use a very wide range of experimental resources to explore how to target skin cancer stem cells therapeutically, and how skin stem cell health and maintenance could thwart chronological aging.

Read about George Murphy's research in the feature story Healing Without Scars.

Read about Markus Frank's work on limbal cells in the feature Can We Restore Sight?

So far, scientists in the HSCI Skin Program have:

Sign up for the monthly HSCI Newsletterto get email updates about our research.

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Getting to the Root of Skin Stem Cells | Brigham Clinical …

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Christine Lian (back) and George Murphy (front) are building a compelling case for why skin stem cells may be at the root of skin regeneration and the development of cancer.

In the 1980s, when George Murphy, MD, was just beginning his career at the Brigham, he had the opportunity to assist Brigham reconstructive plastic surgeon Dennis Orgill, MD, PhD, and MIT materials scientist Ioannis Yannas, PhD, on the development of a biodegradable membrane they hoped would act as an artificial skin and facilitate wound healing. Made from bovine collagen and a jelly-like substance derived from sharks (glycosaminoglycan), the membrane had the capacity to thwart the formation of dysfunctional scar tissue and promote true regenerative skin healing. (Known as Integra, the membrane is used all over the world today for wound healing.) The investigators didnt realize it at the time, but they had stumbled upon the healing power of skin stem cellsseveral decades before skin stem cells had been discovered.

In the years ahead, seminal discoveries and experiments by Brigham investigators including Murphy, who is now the director of Dermatopathology, and his colleague and collaborator Christine Lian, MD, would build a compelling case for why skin stem cells may be at the root of two seemingly unrelated phenomena: skin regeneration and the development of cancer.

In 2004, Murphy began his second foray into the world of skin stem cells by working intensively with Natasha Frank, MD, of the Division of Genetics; Markus Frank, MD, of the Renal Division; and Tobias Schatton, PhD, of the Department of Dermatology. In 2007, the team pioneered a discovery that made the cover of the journal Nature: the first identification of stem cells responsible for malignant melanoma, a potentially deadly yet poorly understood form of skin cancer.

Like queen bees in a hive of hundreds of workers, relatively rare malignant skin stem cells are crucial to the genesis and maintenance of an entire tumor, said Murphy. Stem cells tend to be covert and there is a scarcity of biomarkers with which to detect them. The molecule that was discoveredABCB5could identify stem cells in normal skin and identified a cell in malignant melanoma that, although only a small component of melanoma, appeared to drive the tumor.

These insights have led to a clear and concise goal in cancer therapeutics: target and eliminate malignant stem cells. But Murphy and colleagues want to take this goal one step further by targeting precursor cancer skin stem cells before melanoma poses danger.

Melanoma is curable when its very early. But when it gets to be the volume of something potentially no larger than a lentil, it can metastasize and kill you, said Murphy. This switchfrom a curable stage to a deadly stageis critical to study.

In contrast to stem cells that have gone awry, normal skin stem cells are essential to the health and well-being of mature, functional skin. The ability to manipulate the fate of normal skin stem cells could also hold the secret to regenerative wound healing. How to control stem cell behavior and destiny, therefore, became the burning question.

Murphy and Lian credit the origins of their collaborative partnership to strategic adjacency (being in the same building) and luck.

It was both science and serendipity that brought us together, said Lian. Now that the potential problems can be seen more clearly, our goal is to home in on the stem cell epigenome in ways that will lead to new and effective therapies for our patients. Together, we are aggressively pursuing this goal.

By 2011, Lian had joined the Program in Dermatopathology, bringing with her a fundamental insight into the role of the epigenome, the external coating that envelops the DNA molecule and regulates its behavior (or misbehavior, in the case of a malignancy).

Lian had joined the Brigham in 2004 as a postdoc, where she worked on the second floor of 221 Longwood Ave., striving to bring insights from epigenomics to bear on clinical work. Lian was especially interested in melanoma, in part because of the tremendous socioeconomic impact of the disease. She soon heard about Murphywho was working just two floors above. Their proximity helped bring about a new collaboration.

That collaboration led to the creation of the Dermatopathology Stem Cell/Epigenomics Laboratory. In 2012, they published a paper together in the journal Cell, exploring the role of a critical epigenetic marka chemical punctuation mark that tells a cell how genes should be readin melanoma skin stem cells. The team found that the loss of this key epigenetic mark was a hallmark of melanoma, with both diagnostic and prognostic implications, and could be identified in precursor cells. This landmark discovery suggested that the skin stem cell epigenome may be a key to both controlling melanoma and skin regeneration.

The epigenome controls the way DNA behaves, just like a mutation. But unlike a mutation, changes to the epigenome are reversible, said Lian. This opens up exciting therapeutic possibilities and avenues to pursue.

Lian, Murphy and their colleagues are intent on identifying novel ways to target and destroy skin cancer stem cells as well as to control and regulate skin stem cells capable of regenerative healing through therapeutic modulation of the epigenome.

In addition, they are pursuing questions related to aging and transplant rejection through collaboration with multidisciplinary experts and by leveraging diverse, cutting-edge technologies, including next-generation-epigenetic sequencing, three-dimensional bioprinting, and highly multiplexed image capture to simultaneously visualize critical stem cell molecules. The lab works closely with the Harvard Stem Cell Institute, and major collaborative proposals are planned and underway in areas including regenerative wound healing, cancer prevention and epigenomic therapeutics.

Weve assembled a multidisciplinary team interested in the conjunctiva of the eye, the dental cavity, the regenerative properties of salamanders and more, said Murphy. We have found investigators across the Boston area who share their interest in the role of skin stem cells but have expertise and interests in far-ranging areas.

Lian and Murphy are optimistic that this team, with its wide-ranging expertise, will take the steps needed to understand and control those rare cells thatbothdrive cancers and hold the key to tissue regeneration.

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New insights into cardiac stem cells could lead to heart …

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University of Arizona researchers Churko and colleagues describe new findings of gene expression patterns in cardiac stem cells, which could be used to create heart regeneration therapies.

Heart disease affects millions of people each year and has the potential to impair heart function by damaging heart muscle. Although many preventative therapies are available, once damage has occurred to the cells of the heart, there are not many treatment options available. The heart has a limited capacity to heal itself, but one option that could result from new research into stem cell therapies is regenerative therapy, leading to cardiac regeneration. However, the processes involved in stem cell differentiation into various heart muscle tissues are not well understood.

In a new study published in Nature Communications, University of Arizona researchers Churko and colleagues investigate the gene expression patterns that are responsible for the differentiation of heart cells. This will clarify how heart cells develop and respond to drugs or other factors.

The researchers found that heart muscle cells vary in gene expression as they mature, between days 14 and 45. Younger cells have gene expression profiles more like those of cells of the heart atrium, whereas more mature cells have gene expression profiles more like those of the heart ventricle. Churko and colleagues also identified one gene, NR2F2, that, when overexpressed blunted expression of the specific genes that are expressed within muscle cells and heart cells, and led to increased expression of the genes associated with pluripotent stem cells and neuronal cells.

Churko and colleagues findings will help other researchers working on heart stem cells and regenerative therapy. By understanding the genetic expression patterns that lead to or characterize the differentiation of stem cells into heart muscle cells, researchers will be able to guide pluripotent stem cells into becoming cardiac cells. Ultimately, this will lead to better treatment for patients with heart disease and a damaged heart.

Written by C.I. Villamil

Reference: Churko et al. 2018. Defining human cardiac transcription factor hierarchies using integrated single-cell heterogeneity analysis. Nature communications 9:4906.

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Cell Regeneration Perth | Cell Rejuvenation and Cell Therapy

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There are a lot of theories as to why people change as they get older. Some claim that aging is caused by injuries from ultraviolet light over time, wear and tear on the body, or by-products ofmetabolism. Other theories view aging as a predetermined process controlled by genes.

No single process can explain all the changes of aging. Aging is a complex process that varies as to how it affects different people and even different organs. Most gerontologists (people who study aging) feel that aging is due to the interaction of many lifelong influences. These influences include heredity, environment, culture, diet, exercise and leisure, past illnesses, and many other factors.

Unlike the changes of adolescence, which are predictable to within a few years, each person ages at a unique rate. Some systems begin aging as early as age 30. Other aging processes are not common until much later in life.

Although some changes always occur with aging, they occur at different rates and to different extents. There is no way to predict exactly how you will age.

Some studies have shown that Cell Regeneration treatments have a better effect on people over the age of 35, however this has no clinical evidence to back it up. What we do know is that as we age our bodies do not renew cell turnover at the same rate as it did in our younger years. And there appears to be no end age for these treatments to have some effect.

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Pluripotent Stem Cells 101 Boston Children’s Hospital

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Pluripotent stem cells are master cells. Theyre able to make cells from all three basic body layers, so they can potentially produce any cell or tissue the body needs to repair itself. This master property is called pluripotency. Like all stem cells, pluripotent stem cells are also able to self-renew, meaning they can perpetually create more copies of themselves.

There are several types of pluripotent stem cells, including embryonic stem cells. At Childrens Hospital Boston, we use the broader term because pluripotent stem cells can come from different sources, and each method creates a cell with slightly different properties.

But all of them are able to differentiate, or mature, into the three primary groups of cells that form a human being:

Right now, its not clear which type or types of pluripotent stem cells will ultimately be used to create cells for treatment, but all of them are valuable for research purposes, and each type has unique lessons to teach scientists. Scientists are just beginning to understand the subtle differences between the different kinds of pluripotent stem cells, and studying all of them offers the greatest chance of success in using them to help patients.

Types of pluripotent stem cells:

All four types of pluripotent stem cells are being actively studied at Childrens.

Induced pluripotent cells (iPS cells):Scientists have discovered ways to take an ordinary cell, such as a skin cell, and reprogram it by introducing several genes that convert it into a pluripotent cell. These genetically reprogrammed cells are known as induced pluripotent cells, or iPS cells. The Stem Cell Program at Childrens Hospital Boston was one of the first three labs to do this in human cells, an accomplishment cited as the Breakthrough of the Year in 2008 by the journal Science.

iPS cells offer great therapeutic potential. Because they come from a patients own cells, they are genetically matched to that patient, so they can eliminate tissue matching and tissue rejection problems that currently hinder successful cell and tissue transplantation. iPS cells are also a valuable research tool for understanding how different diseases develop.

Because iPS cells are derived from skin or other body cells, some people feel that genetic reprogramming is more ethical than deriving embryonic stem cells from embryos or eggs. However, this process must be carefully controlled and tested for safety before its used to create treatments. In animal studies, some of the genes and the viruses used to introduce them have been observed to cause cancer. More research is also needed to make the process of creating iPS cells more efficient.

iPS cells are of great interest at Childrens, and the lab of George Q. Daley, MD, PhD, Director of Stem Cell Transplantation Program, reported creating 10 disease-specific iPS lines, the start of a growing repository of iPS cell lines.

Embryonic stem cells:Scientists use embryonic stem cell as a general term for pluripotent stem cells that are made using embryos or eggs, rather than for cells genetically reprogrammed from the body. There are several types of embryonic stem cells:

1. True embryonic stem cell (ES cells)These are perhaps the best-known type of pluripotent stem cell, made from unused embryos that are donated by couples who have undergone in vitro fertilization (IVF). The IVF process, in which the egg and sperm are brought together in a lab dish, frequently generates more embryos than a couple needs to achieve a pregnancy.

These unused embryos are sometimes frozen for future use, sometimes made available to other couples undergoing fertility treatment, and sometimes simply discarded, but some couples choose to donate them to science. For details on how theyre turned into stem cells, visit our page How do we get pluripotent stem cells?

Pluripotent stem cells made from embryos are generic and arent genetically matched to a particular patient, so are unlikely to be used to create cells for treatment. Instead, they are used to advance our knowledge of how stem cells behave and differentiate.

2. Stem cells made by somatic cell nuclear transfer (ntES cells)The term somatic cell nuclear transfer (SCNT) means, literally, transferring the nucleus (which contains all of a cells genetic instructions) from a somatic cellany cell of the bodyto another cell, in this case an egg cell. This type of pluripotent stem cell, sometimes called an ntES cell, has only been made successfully in lower animals. To make ntES cells in human patients, an egg donor would be needed, as well as a cell from the patient (typically a skin cell).

The process of transferring a different nucleus into the egg reprograms it to a pluripotent state, reactivating the full set of genes for making all the tissues of the body. The egg is then allowed to develop in the lab for several days, and pluripotent stem cells are derived from it. (Read more in How do we get pluripotent stem cells?)

Like iPS cells, ntES cells match the patient genetically. If created successfully in humans, and if proven safe, ntES cells could completely eliminate tissue matching and tissue rejection problems. For this reason, they are actively being researched at Childrens.

3. Stem cells from unfertilized eggs (parthenogenetic embryonic stem cells)Through chemical treatments, unfertilized eggs can be tricked into developing into embryos without being fertilized by sperm, a process called parthenogenesis. The embryos are allowed to develop in the lab for several days, and then pluripotent stem cells can be derived from them (for more, see How do we get pluripotent stem cells?)

If this technique is proven safe, a woman might be able to donate her own eggs to create pluripotent stem cells matching her genetically that in turn could be used to make cells that wouldnt be rejected by her immune system.

Through careful genetic typing, it might also be possible to use pES cells to create treatments for patients beyond the egg donor herself, by creating master banks of cells matched to different tissue types. In 2006, working with mice, Childrens researchers were the first to demonstrate the potential feasibility of this approach. (For details, see Turning pluripotent stem cells into treatment).

Because pES cells can be made more easily and more efficiently than ntES cells, they could potentially be ready for clinical use sooner. However, more needs to be known about their safety. Concerns have been raised that tissues derived from them might not function normally.

Read more about pluripotent stem cells by following these links:

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Pluripotent Stem Cells 101 Boston Children's Hospital

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categoriaSkin Stem Cells commentoComments Off on Pluripotent Stem Cells 101 Boston Children’s Hospital | dataMarch 5th, 2019
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StemFactor – Skin Growth Factor Serum

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"I started using Osmosis about two weeks ago and only off and on. I had several skin tags on my face, which a doctor want to charge 100 dollars per tag to remove. The StemFactor dried them up and I have been removing them when washing. Unbelievable. I thought I had to live with and the best part, no hyperpigmentation. Thanks!" ~ B Andrews

Esthetician Marianne Kehoe, has worked with thousands of clients and numerous products for more than 20 years. "Between Catalyst and StemFactor, the results Im seeing in my practice are phenomenal, repeatedly, according to Kehoe, including with post-operative scars and people who have been exposed to the California sun for years."

"Over the past month I have noticed a significant improvement in my skin through using Osmosis skincare. I began with a starter pack then introduced Stem Factor - this has resulted in a huge difference to both the acne prone areas as well as contributing to the overall glow of my skin. I have had problems with my skin for a number of years and in particular Osmosis Stem Factor is the only product I've found that continues to improve skin appearance." ~ Emma

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StemFactor - Skin Growth Factor Serum

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Stem Cell Therapy for the Face, Skin, and Hair Clinic …

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Unwelcome Signs of Aging

Saggy cheeks and eyelids, sallow looking skin, pronounced cellulite, thinning hair or even loss of hair those are just some examples for unpleasant changes of an aging face and body. Are these unavoidable signs of aging or do these changes of the body possibly have other reasons?

Unfortunately or rather luckily it is not possible to stop time and to spend life in eternal youth. However, premature or especially distinctive aging processes may be triggered by lifestyle, burdening circumstances, or illness.

If the body is suffering from deficiency symptoms due to chronic stress or illness, the skins biological quality and elasticity are decreasing and the underlying tissue, the muscles, and other body structures are degenerating. Thinning hair, extensive hair loss, or alopecia (circular hair loss) may also be explained by illness or age.

It is our task to determine why the body is aging ahead of time and furthermore to work against the degenerative aging processes in order to eliminate their unwelcome consequences. All our treatments are focused on rejuvenating by using the potential of the bodys own components. We especially use the impressive regenerative power of stem cells from body fat and growth factors found in the blood. Bioidentical hormones, which are structurally identical to natural hormones, support your body by rebuilding a stable hormonal balance, which is important for the bodily systems to function.

Thanks Dr. Heinrich, I again like to look in the mirror!

We offer promising therapies with stem cells and growth factors both for regeneration of skin as well as hair. Hormone deficiencies are often the reason for unwelcome changes of the body.

In most cases invasive surgical interventions such as facelifts and eyelid corrections, removing excess tissue, and hair transplants are not suitable. Instead it is more important to treat the cause of these issues and regenerate the underlying tissue and skin to gently replenish its volume.

We are strictly opposed to synthetic fillers (e.g., silicone, hyaluronic acid) since those kinds of therapies are solely used to improve the visible symptoms without having a regenerative effect and without treating the actual cause.

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Stem Cell Therapy for the Face, Skin, and Hair Clinic ...

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Reprogrammed stem cells to treat spinal-cord injuries …

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Scientists in Japan now have permission to inject 'reprogrammed' stem cells into people with spinal-cord injuries.

An upcoming trial will mark the first time that induced pluripotent stem (iPS) cells have been used to treat spinal-cord injuries, after a committee at Japans health ministry approved the study on 18 February. IPS cells are created by inducing cells from body tissue to revert to an embryonic-like state, from which they can develop into other cell types.

Hideyuki Okano, a stem-cell scientist at Keio University in Tokyo, will coax donor iPS cells into becoming neural precursor cells, which can develop into neurons and glial cells. His team will then inject two million of the precursor cells per patient into the site of spinal injury around 24 weeks after the injury occurs. .

Okano has demonstrated that the procedure can regenerate neurons in monkeys with injured spinal cords and increase their mobility1.

Okanos team will carry out the experimental therapy in four people, monitoring them to ensure it is safe and effective before deciding whether to start a larger clinical trial with more participants. The first patient is expected to be treated in the second half of this year.

IPS cells have been used in a handful of other clinical applications, including to treat age-related macular degeneration in 2014 and 2017, and Parkinsons disease in 2018.

A clinical trial in the United States is also testing a treatment for spinal-cord injuries using embryonic stem cells. The study has so far only led to minor improvements in a few patients, and has yet to demonstrate that it works in a controlled trial.

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Reprogrammed stem cells to treat spinal-cord injuries ...

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