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Spinal Cord Injury Research Advances with New Stem Cells

By Dr. Matthew Watson

At Spinal Cord, were excited to share that researchers at the University of California, San Diego successfully created spinal cord neural stem cells (NSCs) that could have clinical applications in spinal cord injury and disorder treatments.

The spinal cord injury research, conducted by postdoctoral scholar Hiromi Kumamaru and Professor of Neuroscience and Director of the UCSD Translational Neuroscience Institute Mark Tuszynski, grafted the cultured cells into the spinal cords of rats with spinal cord injuries (SCIs).

Kumamaru says about the spinal cord injury research:

In grafts, these cells could be found throughout the spinal cord, dorsal to ventral. They promoted regeneration after spinal cord injury in adult rats, including corticospinal axons, which are extremely important in human voluntary motor function. In rats, they supported functional recovery.

These diverse cells are derived from immature self-replicating human stem cells known as human pluripotent stem cells (hPSCs), which morph into different types of stem cells that could disperse throughout the spinal cord. According to the researchers, these pluripotent cells could serve as a scalable source of replacement cells for individuals with spinal cord injuries.

In the Universitys press release, Tuszynski says that the new cells could serve as source cells for human clinical trials in three to five years. First, however, it first needs to be determined whether the cells are safe over long-time periods via studies on rodents and non-human primates and that the results are replicable.

According to the Universitys press release on the new stem cell research:

The achievement, described in the August 6 online issue of Nature Methods, advances not only basic research like biomedical applications of in vitro disease modeling, but may constitute an improved, clinically translatable cell source for replacement strategies in spinal cord injuries and disorders.

The hope is that the cultured spinal cord neural stem cells from this stem cell research will benefit people with other spinal cord dysfunction disorders via modeling and drug screening. According to UCSD, such disorders would include amyotrophic lateral sclerosis, progressive muscular atrophy, hereditary spastic paraplegia and spinocerebellar ataxia, a group of genetic disorders characterized by progressive discoordination of gait, hands and eye movement.

Although significant research has been done to explore the potential use of hPSC stem cells in creating new cells to repair diseased or damaged spinal cords, historically, progress has been slow and limited.

It is one of the goals of the Spinal Cord team to help keep you and your family informed about the newest medical advances in spinal cord injury research. We recently shared about exciting advances in gene therapy research that helped to restore hand function in rats with SCIs, as well as the use of olfactory ensheathing cells (cells from the bodys system that enables you to perceive smells) to trigger spinal cord nerve regeneration.

Please be sure to subscribe to our blog to get the latest updates on stem cell and other spinal cord injury research.

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Stem Cell Therapy for ALS Patients

By Dr. Matthew Watson

Learn about what stem cells are, why they are important and how they are going to revolutionize healing and medical care in Canada.

Not all conditions are effectively treated by PRP injections or stem cell therapy, and with ongoing clinical trials its important to realize what stem cells can and cannot help with. Weve built a comprehensive list of the different types of conditions that stem cell therapy shows promise for, however if you dont find it listed wed recommend checking outDanish health website Doc24.dk. Regular maintenance of health is key to making sure long-term issues dont arise as we age, and part of that is a rich, balanced diet and careful supplementation.

Research on human embryos in general, and stem cell research in particular, has been the subject of public debate in Canada since the late 1980s. In 2002, the Canadian Institute of Health Research (CIHR) issued guidelines for research on human embryonic stem cell lines, which have been revised and reissued several times since 2005 (most recently in 2007). These guidelines regulate the allocation of state funds in the field of research on human embryonic stem cells and concern both the handling of existing stem cell lines and the establishment of new stem cell lines.

The guidelines specify a number of important conditions that must be fulfilled in order for research projects to be eligible for funding. These include, but are not limited to:

The Stem Cell Oversight Committee (SCOC) was set up to ensure that research projects comply with the provisions of the Directive and to address the complex ethical issues surrounding research projects. Any project applying for government funding in the field of stem cell research must first be positively evaluated by the SCOC.

In addition to the regulation of state funding, the Assisted Human Reproduction Act came into force in 2004, which broadly regulates the field of reproductive medicine. Unlike the guidelines of the CIHR, it is not merely a guideline for state funding of certain research activities, but a law that places certain activities under state control and generally prohibits others. Research on human embryos is one of the controlled activities of the Assisted Human Reproduction Act. According to 8 Para. 3, the approval according to 10 Para. 2 requires the consent of the donor after clarification of the intended use. The Assisted Human Reproduction Agency of Canada (AHRAC), established by law, is responsible for granting authorisations and monitoring research activities.

The extraction of ES cells also falls under this section and is therefore permitted in Canada. The use of in vitro embryos for research purposes, including the derivation of stem cells, is subject to the following conditions under the Assisted Human Reproduction Act:

The production of a human clone is prohibited according to 5 a Assisted Human Reproduction Act. This provision also includes so-called therapeutic cloning by nuclear transfer. According to 5 b, the creation of embryos for purposes other than the creation of a human being or the improvement of artificial reproduction procedures is also prohibited. The law does not apply to the handling of already established human embryonic stem cell lines.

The CBC news network and other media responded to Twitter posts and a YouTube live video about unapproved treatments that lately came up. Patients that suffer from chronic pain or disease could benefit from stem-cell therapies. Canadians who have been treated more open by their federal and other regulatory laws about unlicensed stem cell therapies are asking for the legalization or this procedure.

A new company now made it their mission to offer direct-to-customer opportunities for trainees and people in general which can mean a big advantage for a patient. Unproven stories about this training in marketing and science services are offering support for approved stem-cell professionals.

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Spinal Cord Injury Center – Treatments, Research …

By Dr. Matthew Watson

Spinal Cord Injuries Are Not JustCaused by Trauma

When you think of spinal cord injury (SCI), traumatic events like a serious car accident may come to mind. While its true that car accidents are the leading cause of traumatic SCI, you may be surprised that non-traumatic diseasessuch as a spinal tumorcan also cause SCI.

SCI involves damage to the spinal cord that temporarily or permanently changes how it functions. SCI is divided into 2 categories: traumatic or non-traumatic. Even if the cause of SCI is non-traumatic, that doesnt lessen its impact or severitythe aftermath of SCI can have devastating effects on a persons life.Falls are the second most common cause of traumatic spinal cord injury. Photo Source: 123RF.com.Traumatic Spinal Cord Injury

Traumatic SCI occurs more often in men than womennearly 80% of cases affect men. People of all ages may experience SCI, but certain activities tend to affect different age groups more. For example, high-impact events like car accidents and sports injuries tend to occur more often in younger people. On the other hand, traumatic SCI caused by a fall is more common in adults over age 60.

Regardless of the cause, traumatic SCI occurs most frequently in the cervical spine (about 60% of cases involve the neck), followed by thoracic spine (32% involve the mid-back). Only 9% of cases occur in the lumbosacral spine, or low back and tailbone.

Understanding the Traumatic Spinal Cord Injury CascadeA traumatic SCI doesnt simply damage your spinal cord at the point of initial impact. In traumatic SCI, the primary injury (that is, the initial traumatic event that caused the SCI) may damage cells and dislocate your spinal vertebrae, which causes spinal cord compression. The primary injury also triggers a complex secondary injury cascade, which causes a series of biological changes that may occur weeks and months after the initial injury.

During the secondary injury cascade, the following processes occur:

This cascade changes the spinal cords structure and how it normally operates. Ultimately, this secondary injury cascade may interfere with the spinal cords ability to recover itself. This means a person with traumatic SCI may experience permanent nerve pain and dysfunction because of their injury.

Non-traumatic Spinal Cord InjuryTraumatic events arent the only causes of spinal cord damageSCI can also be caused by non-traumatic diseases in the spine. Spinal tumors are the leading cause of non-traumatic SCI, but infections and degenerative disc disease can also damage your spinal cord.

Though most people connect traumatic events to SCI, non-traumatic causes of SCI are a much more likely cause. To highlight just how common non-traumatic cases are versus their traumatic counterparts, consider the incidence of traumatic SCI in North America: 39 cases per million people. On the other hand, the incidence of non-traumatic SCI is 1,227 cases per million people for Canada alone (data for the rest of North America is not available).

A Healthy Research Outlook to Improve Spinal Cord Injury OutcomesOver the past 30 years, spine researchers have made great strides in developing successful protective and regenerative therapies to improve the health of the spinal cord and the survival rate of people with SCIbut the work is far from over. Current studies and clinical trials are examining innovative medical, surgical and cell-based treatments to further the medical communitys understanding of SCI, which will improve the quality of life and preserve a brighter future for people who experience these injuries.

Suggested Additional ReadingA special issue of the Global Spine Journal set forth guidelines for the Management of Degenerative Myelopathy and Acute Spinal Cord Injury, which is summarized on SpineUniverse in Summary of the Clinical Practice Guidelines for the Management of Degenerative Cervical Myelopathy and Traumatic Spinal Cord Injury.

Sources:Ahuja CS, Wilson JR, Nori S, et al. Traumatic spinal cord injury. Nature Reviews Disease Primers. 3, 17018. https://www.nature.com/articles/nrdp201718. Accessed January 10, 2018.

Spinal Cord Injury. Facts and figures at a glance. National SCI Statistical Center (NSCI SC). 2017. https://www.nscisc.uab.edu/. Accessed January 10, 2018.

Updated on: 01/27/19

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C3, C4, & C5 Vertebrae Spinal Cord Injury | SpinalCord.com

By Dr. Matthew Watson

The C3, C4, and C5 vertebrae form the midsection of the cervical spine, near the base of the neck. Injuries to the nerves and tissue relating to the cervical regionare the most severe of all spinal cord injuries because the higher up in the spine an injury occurs, the more damage that is caused to the central nervous system. Depending on the how severe the damage to the spinal cord is, the injury may be noted as complete or incomplete.

The C2 - C3 junction of the spinal column is important, as this is where flexion and extension occur (flexion is the movement of the chin toward the chest and extension is the backward movement of the head). Patients with spinal cord damage at the C3 level will have limited mobility in both their flexion and extension.

Symptoms of a spinal cord injury corresponding toC3 vertebrae include:

The portion of the spinal cord which relatesto the C4 vertebra directly affects the diaphragm. Patients with C4 spinal cord injuries typically need 24 hour-a-day support to breathe and maintain oxygen levels.

Symptoms of a spinal cord injury corresponding toC4 vertebrae include:

Damage to the spinal cord at the C5 vertebra affects the vocal cords, biceps, and deltoid muscles in the upper arms. Unlike some of the higher cervical injuries, a patient with a C5 spinal cord injury will likely be able to breath and speak on their own.

Symptoms of a spinal cord injury corresponding to C5 vertebrae include:

The most common causes of cervical spinal cord injuries are:

Unfortunately, there is no treatment which will completely reverse the damage frominjuries to the spinal cord at the C3 - C5 levels. Medical care is focused on preventingfurther damage to the spinal cord and utilization of remaining function.

Current treatments available for patients are:

It is an unfortunate truth that there are not many options to date to completely recover from a cervical spinal cord injury. Medical researchers are continuously looking into new drug therapies to help regain sensory and motor function. The use of stem cells is seen more and more in research as these cells are specialized enough to possibly regenerate damaged spinal cord tissues. Lab study results show greater sensory and motor function in those patients treated with stem cells for spinal cord damage.

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Bone Marrow for Spine and Orthopaedic Stem Cell Treatment …

By Dr. Matthew Watson

Stem cells are the next frontier in the treatment of orthopaedic and spinal disorders, and the Cary Orthopaedics team is leading the way.

Using stem cells harvested from an adult patients own bone marrow,Dr. Sameer Mathurand Dr. Nael Shanti both board-certified orthopaedic spinal surgeons have developed a minimally invasive remedy for those suffering from degenerative disc disease, back pain and spinal arthritis. Applying a similar approach, Cary OrthosDr. Douglas Martini a fellowship-trained, board-certified orthopaedic surgeon specializing in sports medicine has crafted a pain-relief solution for patients living with osteoarthritis and soft tissue injuries.

Multiple research studies have shown a significant reduction in low back and joint pain and improved function after stem cell injections. While these treatments are new, 80% to 90% of patients are already reporting improvement in their symptoms after orthopaedic stem cell treatments.

Many patients suffering from degenerative disc diseases or low back pain are often not ideal candidates for surgery, and some who have chosen to undergo surgery have had unsatisfactory results. Therefore, the typical remedy for chronic orthopaedic conditions is extensive physical therapy combined with oral anti-inflammatory medications. The result: The majority of patients still had to live with pain.

Physicians at Cary Orthopaedics are utilizing orthopaedic stem cell treatment using the patients own bone marrow, the soft, spongy tissue found in the center of bones. Bone marrow in adults contains a rich reservoir of multipotent stem cells also known as Mesenchymal Precursor Cells (MPCs) that can be extracted from the patients pelvis or hip bone. Due to their unique, regenerative composition, these cells can become various types of tissues including soft tissue, bone or cartilage, which make them an excellent resource for repairing and rebuilding damaged tissue, accelerating the healing process and improving overall function.

Thanks to advancements in technology, the removal and harvesting process has become easier and less expensive. Since this is a minimally invasive procedure, it has fewer side effects compared to traditional surgery, and it causes minimal discomfort to the patient.

Bone marrow injections are a breakthrough for patients in pain. Dr. Martini, a sports medicine physician at Cary Orthopaedics, has been active in the sports medicine community, previously serving as team physician for the Carolina Hurricanes, numerous colleges, and local high schools. After 25 years of experience in sports medicine, he realizes the need for improved treatment options for the greying athlete. He has begun incorporating bone marrow aspirate concentrate (BAC) into the treatment of both acute and chronic soft tissue and joint-related injuries. I believe this will be equally helpful to the patient who needs to exercise for overall health benefits as it would be for those who need to stay at their peak athletic performance, says Dr. Martini.

We have found based on our research and experience that stem cell therapy can be very safe and effective when used with the appropriate patient population, said Kevin G. Morrison, PA-C, a member of Dr. Martinis team. All the feedback to this point has been quite positive, both on the process of having the procedure done as well as the early response. But ultimately long-term data will need to be compiled and critically examined.

Much of the previous research into stem cells has centered around placental stem cells, which can also adapt into other types of tissues. However, these have not performed well when put to the test for orthopaedic treatment. Bone marrow aspirate concentrate provides MPCs that can transform into osteocytes, chondrocytes and adipocytes, all of which are important in treating orthopedic conditions.

The latest research around mesenchymal stem cells, specifically bone marrow aspiration, is certainly promising. Dr. Martini will continue to collect more data and review patients responses.

Dr. Mathur has been an instrumental force in elevating the level of patient care at Cary Orthopaedic Spine Center since joining the practice in 2008. Dr. Mathur completed his medical school at the University of Pennsylvania and spinal reconstructive fellowship at the Rush University Medical Center in Chicago. He also taught at Dana Farber Cancer Institute in Boston. Over the last 10 years, in conjunction with the National Institutes of Health, he has conducted significant study of disc degeneration and analysis of the expression of genes that may damage the disc.

In the past decade, there have been several advancements in spinal surgery, but regenerative medicine is the next frontier, said Dr. Mathur. I see so many patients that have low back pain and leg pain from degenerative disc disease. For many, there is no good surgical treatment, and stem cell injections may be a viable option.

As an orthopaedic spine specialist, Dr. Mathur is not only an expert in spinal surgery but also in the diagnosis and treatment of a wide range of spinal problems. His depth of experience allows him to best determine whether a patient would benefit from physical therapy, stem cell injections or surgical intervention. When providing stem cell treatment, Dr. Mathur performs a single injection for all patients, whereas other clinics typically require multiple injections over several weeks.

There is currently extensive, ongoing research on the application of stem cell therapy and tissue regeneration, including an application for spinal cord injury and disc pathology, which is very exciting, said Dr. Shanti, who has dedicated a great deal of time researching the potential impact stem cell therapy can provide for his patients. Dr. Shanti believes stem cell therapy is the next great advancement in healthcare with an application for a wide spectrum of medical conditions.

Recently recognized as Top Orthopaedic Doctor by The Leading Physicians of the World for the outstanding patient care, Dr. Shantis in-depth experience and understanding of the spine allows him to guide his patients especially those with chronic back pain to the most appropriate path of treatment with the shared collaborative goal of pain relief. Dr. Shanti completed his spine surgery fellowship training at the prestigious New England Baptist Hospital, Tufts University program with an emphasis on minimally invasive spine surgery, and he has authored and presented multiple papers and textbooks on the advancement of minimally invasive spine surgery.

Orthopaedic stem cell treatment is an excellent solution for patients with degenerative disc disease and also those suffering from arthritis of the spine, bulging disc, low back pain, facet joint pain or disc with annular tears.

The stem cell injection is a same-day procedure that generally takes one hour to perform. The actual extraction of bone marrow takes up to 10 minutes. The bone marrow extraction site typically the back of the patients hip or pelvis bone is numbed using a mixture of local anesthetics. A suctioned syringe is attached to a long needle that reaches the posterior aspect of the hip. The patient may experience a minimal amount of discomfort during the extraction.

The sample is collected, transferred through a filter, and then placed into a centrifuge for spinning. The speed separates the stem cells and platelets from the bone marrow. This concentration of stem cells is then reintroduced into the degenerative or painful area under image guidance with fluoroscopy to confirm accurate placement.

The harvesting site will be numb for 1 to 2 hours after the procedure, so the patient will need to have transportation home. It is permissible to fly after the treatment, but this may cause increased pain or discomfort.

Stem cell therapy relies on the bodys own regenerative process to heal, which takes time. Patients have seen the benefits in two to three months after treatment; however, many have noticed improvements in symptoms sooner.

The recommended age range for the treatment is 20 to 70 years old. As the body ages, the quality and quantity of stem cells slowly decline. After age 70, patients may experience a sharper decline in stem cells, resulting in less beneficial outcomes.

If you think you might be a candidate for orthopaedic stem cell therapy treatment, contact Cary Orthopaedics to schedule a consultation.

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Become a Donor | The Bone Marrow Foundation

By Dr. Matthew Watson

Jack, diagnosed with Acute Myelogenous Leukemia (AML), and his donor Kristy

To become a donor it just takes a small vial of blood or swab of cheek cells to be typed as a bone marrow/stem cell donor. There are many patients who are desperately waiting to find a donor match. You may be able to save someones life. There are donor registry sites throughout the country.

You must be between the ages of 18 and 60 and in general good health. You should be committed to helping any patient. A simple blood test or cheek cell swab that is given through an authorized National Marrow Donor Program Donor Center or Recruitment Group is needed to obtain your HLA tissue type so it can be entered into the National Registry. You will have to complete a short health questionnaire and sign a form stating that you understand what it means to be listed in the Registry.

The cost for HLA tissue typing ranges from $45 to $96 depending on the Donor Center, the level of testing performed, and the laboratory that analyzes the test results. There may be funding available to offset this cost through the Donor Center. After the initial testing, all medical expenses are covered by the recipient or the recipients insurance. Please contact your local Donor Center for further information.

To find out more information and to become a donor:

Delete Blood Cancer | DKMS1-866-340-3567www.deletebloodcancer.org

The National Marrow Donor Program/Be The Match1-800-654-1247www.marrow.org

The American Bone Marrow Donor Registry1-800-745-2452www.abmdr.org

The Gift of Life1-800-9MARROWwww.giftoflife.org

The Icla da Silva Foundation, Inc.Helping Children and Adults with Leukemia(866) FDN-ICLAwww.icla.org

Every 15 minutes, someone in the United States is diagnosed with a medical condition (over 35,000 people a year) such as leukemia, anemias, myelodysplastic disorders and other life-threatening diseases that require treatment with bone marrow/stem cell transplants. Nearly 70 percent of these patients must rely on an unrelated donor to offer them this precious gift of life. Unfortunately, many patients who are in need of a bone marrow/stem cell transplant cannot find a suitable donor no relatives that match and no match among volunteer donors.

Fortunately, there is an alternative that has been researched and is now proving to be a good option for many of these patientsstem cells from a newborns placental and umbilical cord blood. A newborns umbilical cord and placenta contains stem cells that are the building blocks for mature blood and immune system cells. Umbilical cord blood is collected at the time of birth under controlled conditions, shipped to a blood bank where it is tested, typed and stored.

Two studies published in The New England Journal of Medicine, Volume 351:2276-285 and an editorial by Miguel A. Sanz, M.D., Ph.D. in the same issue, concluded that cord blood should be considered as an acceptable source of stem cells in the absence of a matched bone marrow donor. For many gravely ill patients (who do not have an available donor who is a match), the immediate availability of typed cord blood units is a compelling reason for its use. And for ethnic minorities, who may have unique combinations of HLA types, the chances of finding a donor match with cord blood is greater than from the existing bone marrow donor pool.

If you have a family history of certain diseases you might choose to save your babys cord blood with a private bank. Alternatively, you can donate the cord blood to a public bank. The Bone Marrow Foundation encourages you to direct any questions you have concerning the use and storage of cord blood to your physician or other appropriate health care professional. The following are further resources for more information on public and private banking:

Public Banking National Marrow Donor Program1-800-654-1247www.marrow.org

National Cord Blood ProgramNew York Blood Center310 East 67th StreetNew York, NY 100211-866- 767-NCBP (6227)www.nationalcordbloodprogram.org

Parents Guide to Cord Blood Bankingwww.parentsguidecordblood.org

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Overview of Spinal Cord Disorders – Brain, Spinal Cord …

By Dr. Matthew Watson

Causes of spinal cord disorders include injuries, infections, a blocked blood supply, and compression by a fractured bone or a tumor.

Typically, muscles are weak or paralyzed, sensation is abnormal or lost, and controlling bladder and bowel function may be difficult.

Doctors base the diagnosis on symptoms and results of a physical examination and imaging tests, such as magnetic resonance imaging.

The condition causing the spinal cord disorder is corrected if possible.

Often, rehabilitation is needed to recover as much function as possible.

The spinal cord is the main pathway of communication between the brain and the rest of the body. It is a long, fragile, tubelike structure that extends downward from the base of the brain. The cord is protected by the back bones (vertebrae) of the spine (spinal column). The vertebrae are separated and cushioned by disks made of cartilage.

The spine (spinal column) contains the spinal cord, which is divided into four sections:

Each section is referred to by a letter (C, T, L, or S).

The vertebrae in each section of the spine are numbered beginning at the top. For example, the first vertebra in the cervical spine is labeled C1, the second in the cervical spine is C2, the second in the thoracic spine is T2, the fourth in the lumbar spine is L4, and so forth. These labels are also used to identify specific locations (called levels) in the spinal cord.

Nerves run from a specific level of the spinal cord to a specific area of the body. By noting where a person has weakness, paralysis, sensory loss, or other loss of function, a neurologist can determine where the spinal cord is damaged.

The spine is divided into four sections, and each section is referred to by a letter.

Within each section of the spine, the vertebrae are numbered beginning at the top. These labels (letter plus a number) are used to indicate locations (levels) in the spinal cord.

Along the length of the spinal cord, 31 pairs of spinal nerves emerge through spaces between the vertebrae. Each spinal nerve runs from a specific vertebra in the spinal cord to a specific area of the body. Based on this fact, the skins surface has been divided into areas called dermatomes. A dermatome is an area of skin whose sensory nerves all come from a single spinal nerve root. Loss of sensation in a particular dermatome enables doctors to locate where the spinal cord is damaged.

The surface of the skin is divided into specific areas, called dermatomes. A dermatome is an area of skin whose sensory nerves all come from a single spinal nerve root. (Sensory nerves carry information about such things as touch, pain, temperature, and vibration from the skin to the spinal cord.)

Spinal roots come in pairsone of each pair on each side of the body. There are 31 pairs:

There are 8 pairs of sensory nerve roots for the 7 cervical vertebrae.

Each of the 12 thoracic, 5 lumbar, and 5 sacral vertebrae has one pair of spinal nerve roots.

In addition, at the end of the spinal cord, there is a pair of coccygeal nerve roots, which supply a small area of the skin around the tailbone (coccyx).

There are dermatomes for each of these nerve roots.

Sensory information from a specific dermatome is carried by sensory nerve fibers to the spinal nerve root of a specific vertebra. For example, sensory information from a strip of skin along the back of the thigh is carried by sensory nerve fibers to the 2nd sacral vertebra (S2) nerve root.

A spinal nerve has two nerve roots (a motor root and a sensory root). The only exception is the first spinal nerve, which has no sensory root.

Motor root: The root in the front (the motor or anterior root) contains nerve fibers that carry impulses (signals) from the spinal cord to muscles to stimulate muscle movement (contraction).

Sensory root: The root in the back (the sensory or posterior root) contains nerve fibers that carry sensory information about touch, position, pain, and temperature from the body to the spinal cord.

The spinal cord ends in the lower back (around L1 or L2), but the lower spinal nerve roots continue, forming a bundle that resembles a horses tail (called the cauda equina).

The spinal cord is highly organized (see figure How the Spine Is Organized). The center of the cord consists of gray matter shaped like a butterfly:

The front "wings" (anterior or motor horns) contain nerve cells that carry signals from the brain or spinal cord through the motor root to muscles.

The back (posterior or sensory) horns contain nerve cells that receive signals about pain, temperature, and other sensory information through the sensory root from nerve cells outside the spinal cord.

The outer part of the spinal cord consists of white matter that contains pathways of nerve fibers (called tracts or columns). Each tract carries a specific type of nerve signal either going to the brain (ascending tracts) or from the brain (descending tracts).

Spinal nerves carry nerve impulses to and from the spinal cord through two nerve roots:

Motor (anterior) root: Located toward the front, this root carries impulses from the spinal cord to muscles to stimulate muscle movement.

Sensory (posterior) root: Located toward the back, this root carries sensory information about touch, position, pain, and temperature from the body to the spinal cord.

In the center of the spinal cord, a butterfly-shaped area of gray matter helps relay impulses to and from spinal nerves. Its "wings" are called horns.

Motor (anterior) horns: These horns contain nerve cells that carry signals from the brain or spinal cord through the motor root to muscles.

Posterior (sensory) horns: These horns contain nerve cells that receive signals about pain, temperature, and other sensory information through the sensory root from nerve cells outside the spinal cord.

Impulses travel up (to the brain) or down (from the brain) the spinal cord through distinct pathways (tracts). Each tract carries a different type of nerve signal either going to or from the brain. The following are examples:

Lateral spinothalamic tract: Signals about pain and temperature, received by the sensory horn, travel through this tract to the brain.

Dorsal columns: Signals about the position of the arms and legs travel through the dorsal columns to the brain.

Corticospinal tracts: Signals to move a muscle travel from the brain through these tracts to the motor horn, which routes them to the muscle.

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Human nervous system – The spinal cord | Britannica.com

By Dr. Matthew Watson

The spinal cord is an elongated cylindrical structure, about 45 cm (18 inches) long, that extends from the medulla oblongata to a level between the first and second lumbar vertebrae of the backbone. The terminal part of the spinal cord is called the conus medullaris. The spinal cord is composed of long tracts of myelinated nerve fibres (known as white matter) arranged around the periphery of a symmetrical butterfly-shaped cellular matrix of gray matter. The gray matter contains cell bodies, unmyelinated motor neuron fibres, and interneurons connecting either the two sides of the cord or the dorsal and ventral ganglia. Many interneurons have short axons distributed locally, but some have axons that extend for several spinal segments. Some interneurons may modulate or change the character of signals, while others play key roles in transmission and in patterned reflexes. The gray matter forms three pairs of horns throughout most of the spinal cord: (1) the dorsal horns, composed of sensory neurons, (2) the lateral horns, well defined in thoracic segments and composed of visceral neurons, and (3) the ventral horns, composed of motor neurons. The white matter forming the ascending and descending spinal tracts is grouped in three paired funiculi, or sectors: the dorsal or posterior funiculi, lying between the dorsal horns; the lateral funiculi, lying on each side of the spinal cord between the dorsal-root entry zones and the emergence of the ventral nerve roots; and the ventral funiculi, lying between the ventral median sulcus and each ventral-root zone.

Associated with local regions of the spinal cord and imposing on it an external segmentation are 31 pairs of spinal nerves, each of which receives and furnishes one dorsal and one ventral root. On this basis the spinal cord is divided into the following segments: 8 cervical (C), 12 thoracic (T), 5 lumbar (L), 5 sacral (S), and 1 coccygeal (Coc). Spinal nerve roots emerge via intervertebral foramina; lumbar and sacral spinal roots, descending for some distance within the subarachnoid space before reaching the appropriate foramina, produce a group of nerve roots at the conus medullaris known as the cauda equina. Two enlargements of the spinal cord are evident: (1) a cervical enlargement (C5 through T1), which provides innervation for the upper extremities, and (2) a lumbosacral enlargement (L1 through S2), which innervates the lower extremities. (The spinal nerves and the area that they innervate are described in the section The peripheral nervous system: Spinal nerves.)

The gray matter of the spinal cord is composed of nine distinct cellular layers, or laminae, traditionally indicated by Roman numerals. Laminae I to V, forming the dorsal horns, receive sensory input. Lamina VII forms the intermediate zone at the base of all horns. Lamina IX is composed of clusters of large alpha motor neurons, which innervate striated muscle, and small gamma motor neurons, which innervate contractile elements of the muscle spindle. Axons of both alpha and gamma motor neurons emerge via the ventral roots. Laminae VII and VIII have variable configurations, and lamina VI is present only in the cervical and lumbosacral enlargements. In addition, cells surrounding the central canal of the spinal cord form an area often referred to as lamina X.

All primary sensory neurons that enter the spinal cord originate in ganglia that are located in openings in the vertebral column called the intervertebral foramina. Peripheral processes of the nerve cells in these ganglia convey sensation from various receptors, and central processes of the same cells enter the spinal cord as bundles of nerve filaments. Fibres conveying specific forms of sensation follow separate pathways. Impulses involved with pain and noxious stimuli largely end in laminae I and II, while impulses associated with tactile sense end in lamina IV or on processes of cells in that lamina. Signals from stretch receptors (i.e., muscle spindles and tendon organs) end in parts of laminae V, VI, and VII; collaterals of these fibres associated with the stretch reflex project into lamina IX.

Virtually all parts of the spinal gray matter contain interneurons, which connect various cell groups. Many interneurons have short axons distributed locally, but some have axons that extend for several spinal segments. Some interneurons may modulate or change the character of signals, while others play key roles in transmission and in patterned reflexes.

Sensory tracts ascending in the white matter of the spinal cord arise either from cells of spinal ganglia or from intrinsic neurons within the gray matter that receive primary sensory input.

The largest ascending tracts, the fasciculi gracilis and cuneatus, arise from spinal ganglion cells and ascend in the dorsal funiculus to the medulla oblongata. The fasciculus gracilis receives fibres from ganglia below thoracic 6, while spinal ganglia from higher segments of the spinal cord project fibres into the fasciculus cuneatus. The fasciculi terminate upon the nuclei gracilis and cuneatus, large nuclear masses in the medulla. Cells of these nuclei give rise to fibres that cross completely and form the medial lemniscus; the medial lemniscus in turn projects to the ventrobasal nuclear complex of the thalamus. By this pathway, the medial lemniscal system conveys signals associated with tactile, pressure, and kinesthetic (or positional) sense to sensory areas of the cerebral cortex.

Fibres concerned with pain, thermal sense, and light touch enter the lateral-root entry zone and then ascend or descend near the periphery of the spinal cord before entering superficial laminae of the dorsal hornlargely parts of laminae I, IV, and V. Cells in these laminae then give rise to fibres of the two spinothalamic tracts. Those fibres crossing in the ventral white commissure (ventral to the central canal) form the lateral spinothalamic tract, which, ascending in the ventral part of the lateral funiculus, conveys signals related to pain and thermal sense. The anterior spinothalamic tract arises from fibres that cross the midline in the same fashion but ascend more anteriorly in the spinal cord; these fibres convey impulses related to light touch. At medullary levels the two spinothalamic tracts merge and cannot be distinguished as separate entities. Many of the fibres, or collaterals, of the spinothalamic tracts terminate upon cell groups in the reticular formation, while the principal tracts convey sensory impulses to relay nuclei in the thalamus.

Impulses from stretch receptors are carried by fibres that synapse upon cells in deep laminae of the dorsal horn or in lamina VII. The posterior spinocerebellar tract arises from the dorsal nucleus of Clarke and ascends peripherally in the dorsal part of the lateral funiculus. The anterior spinocerebellar tract ascends on the ventral margin of the lateral funiculus. Both tracts transmit signals to portions of the anterior lobe of the cerebellum and are involved in mechanisms that automatically regulate muscle tone without reaching consciousness.

Tracts descending to the spinal cord are involved with voluntary motor function, muscle tone, reflexes and equilibrium, visceral innervation, and modulation of ascending sensory signals. The largest, the corticospinal tract, originates in broad regions of the cerebral cortex. Smaller descending tracts, which include the rubrospinal tract, the vestibulospinal tract, and the reticulospinal tract, originate in nuclei in the midbrain, pons, and medulla oblongata. Most of these brainstem nuclei themselves receive input from the cerebral cortex, the cerebellar cortex, deep nuclei of the cerebellum, or some combination of these.

In addition, autonomic tracts, which descend from various nuclei in the brainstem to preganglionic sympathetic and parasympathetic neurons in the spinal cord, constitute a vital link between the centres that regulate visceral functions and the nerve cells that actually effect changes.

The corticospinal tract originates from pyramid-shaped cells in the premotor, primary motor, and primary sensory cortex and is involved in skilled voluntary activity. Containing about one million fibres, it forms a significant part of the posterior limb of the internal capsule and is a major constituent of the crus cerebri in the midbrain. As the fibres emerge from the pons, they form compact bundles on the ventral surface of the medulla, known as the medullary pyramids. In the lower medulla about 90 percent of the fibres of the corticospinal tract decussate and descend in the dorsolateral funiculus of the spinal cord. Of the fibres that do not cross in the medulla, approximately 8 percent cross in cervical spinal segments. As the tract descends, fibres and collaterals branch off at all segmental levels, synapsing upon interneurons in lamina VII and upon motor neurons in lamina IX. Approximately 50 percent of the corticospinal fibres terminate within cervical segments.

At birth, few of the fibres of the corticospinal tract are myelinated; myelination takes place during the first year after birth, along with the acquisition of motor skills. Because the tract passes through, or close to, nearly every major division of the neuraxis, it is vulnerable to vascular and other kinds of lesions. A relatively small lesion in the posterior limb of the internal capsule, for example, may result in contralateral hemiparesis, which is characterized by weakness, spasticity, greatly increased deep tendon reflexes, and certain abnormal reflexes.

The rubrospinal tract arises from cells in the caudal part of the red nucleus, an encapsulated cell group in the midbrain tegmentum. Fibres of this tract decussate at midbrain levels, descend in the lateral funiculus of the spinal cord (overlapping ventral parts of the corticospinal tract), enter the spinal gray matter, and terminate on interneurons in lamina VII. Through these crossed rubrospinal projections, the red nucleus exerts a facilitating influence on flexor alpha motor neurons and a reciprocal inhibiting influence on extensor alpha motor neurons. Because cells of the red nucleus receive input from the motor cortex (via corticorubral projections) and from globose and emboliform nuclei of the cerebellum (via the superior cerebellar peduncle), the rubrospinal tract effectively brings flexor muscle tone under the control of these two regions of the brain.

The vestibulospinal tract originates from cells of the lateral vestibular nucleus, which lies in the floor of the fourth ventricle. Fibres of this tract descend the length of the spinal cord in the ventral and lateral funiculi without crossing, enter laminae VIII and IX of the anterior horn, and terminate upon both alpha and gamma motor neurons, which innervate ordinary muscle fibres and fibres of the muscle spindle (see below Functions of the human nervous system: Movement). Cells of the lateral vestibular nucleus receive facilitating impulses from labyrinthine receptors in the utricle of the inner ear and from fastigial nuclei in the cerebellum. In addition, inhibitory influences upon these cells are conveyed by direct projections from Purkinje cells in the anterior lobe of the cerebellum. Thus, the vestibulospinal tract mediates the influences of the vestibular end organ and the cerebellum upon extensor muscle tone.

A smaller number of vestibular projections, originating from the medial and inferior vestibular nuclei, descend ipsilaterally in the medial longitudinal fasciculus only to cervical levels. These fibres exert excitatory and inhibitory effects upon cervical motor neurons.

The reticulospinal tracts arise from relatively large but restricted regions of the reticular formation of the pons and medulla oblongatathe same cells that project ascending processes to intralaminar thalamic nuclei and are important in the maintenance of alertness and the conscious state. The pontine reticulospinal tract arises from groups of cells in the pontine reticular formation, descends ipsilaterally as the largest component of the medial longitudinal fasciculus, and terminates among cells in laminae VII and VIII. Fibres of this tract exert facilitating influences upon voluntary movements, muscle tone, and a variety of spinal reflexes. The medullary reticulospinal tract, originating from reticular neurons on both sides of the median raphe, descends in the ventral part of the lateral funiculus and terminates at all spinal levels upon cells in laminae VII and IX. The medullary reticulospinal tract inhibits the same motor activities that are facilitated by the pontine reticulospinal tract. Both tracts receive input from regions of the motor cortex.

Descending fibres involved with visceral and autonomic activities emanate from groups of cells at various levels of the brainstem. For example, hypothalamic nuclei project to visceral nuclei in both the medulla oblongata and the spinal cord; in the spinal cord these projections terminate upon cells of the intermediolateral cell column in thoracic, lumbar, and sacral segments. Preganglionic parasympathetic neurons originating in the oculomotor nuclear complex in the midbrain project not only to the ciliary ganglion but also directly to spinal levels. Some of these fibres reach lumbar segments of the spinal cord, most of them terminating in parts of laminae I and V. Pigmented cells in the isthmus, an area of the rostral pons, form a blackish-blue region known as the locus ceruleus; these cells distribute the neurotransmitter norepinephrine to the brain and spinal cord. Fibres from the locus ceruleus descend to spinal levels without crossing and are distributed to terminals in the anterior horn, the intermediate zone, and the dorsal horn. Other noradrenergic cell groups in the pons, near the motor nucleus of the facial nerve, project uncrossed noradrenergic fibres that terminate in the intermediolateral cell column (that is, lamina VII of the lateral horn). Postganglionic sympathetic neurons associated with this system have direct effects upon the cardiovascular system. Cells in the nucleus of the solitary tract project crossed fibres to the phrenic nerve nucleus (in cervical segments three through five), the intermediate zone, and the anterior horn at thoracic levels; these innervate respiratory muscles.

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Where Do Stem Cells Come From? | Basics Of Stem Cell …

By Dr. Matthew Watson

Where do stem cells come from? Learn the basics of master cells to better understand their therapeutic potential.

In this article:

Where do stem cells come from? You have probably heard of thewonders of stem cell therapy. Not only do stem cells make research for future scientific breakthroughs possible, but they also provide the basis for many medical treatments today. So, where exactly are they from, and how are they different from regular cells? The answer depends on the types of stem cells in question.

There are two main types of stem cells adult and embryonic:

Beyond the two broader categories, there are sub-categories. Each has its own characteristics. For researchers, the different types of stem cells serve specific purposes.

Many tissues throughout the adult human body contain stem cells. Scientists previously believed adult stem cells to be inferior to human embryonic stem cells for therapeutic purposes. Theydid not believe adult stem cells to be as versatile as embryonic stem cells (ESCs), because they are not capable of becoming all 200 cell types within the human body.

While this theoryhas notbeen entirely disproved, encouraging evidence suggests that adult stem cells can develop into a variety of new types of cells. They can also affect repair through other mechanisms.

In August 2017, the number of stem cell publications registered in PubMed, a government database, surpassed 300,000. Stem cells are also being explored in over 4,600 cell therapy clinical trials worldwide. Some of the earliest forms of adult stem cell use include bone marrow and umbilical cord blood transplantation.

It should be noted that while the term adult stem cell is used for this type of cell, it is not descriptive of age, because adult stem cells can come from children. The term simply helps to differentiate stem cells derived from living humans as opposed to embryonic stem cells.

Embryonic stem cells are controversial because they are made from embryos that are created but not used by fertility clinics.

Because adult stem cells are somewhat limited in the cell types they can become, scientists developed a way to genetically reprogram cells into what is called an inducedpluripotent stem cell or iPS cell. In creating inducedpluripotent stem cells, researchers hope to blend the usefulness of adult stem cells with the promise of embryonic stem cells.

Both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are known as pluripotent stem cells.

Pluripotent stem cells are a type of cell that has the capacity to divide indefinitely and create any cell found within the three germ layers of an organism: ectoderm (cells forming the skin and nervous system), endoderm (cells forming pancreas, liver, endocrine gland, and gastrointestinal and respiratory tracts), and mesoderm (cells forming connective tissues, and other related tissues, muscles, bones, most of the circulatory system, and cartilage).

Embryonic stem cells can grow into a much wider range of cell types, but they also carry the risk of immune system rejection in patients. In contrast, adult stem cells are more plentiful, easier to harvest, and less controversial.

Embryonic stem cells come from embryos harvested shortly after fertilization (within 4-5 days). These cells are made when the blastocysts inner cell mass is transferred into a culture medium, allowing them to develop.

At 5-6 days post-fertilization, the cells within the embryo start to specialize. At this time, they no longer are able to become all of the cell types within the human body. They are no longer pluripotent.

Because they are pluripotent, embryonic stem cells can be used to generate healthy cells for disease patients. For example, they can be grown into heart cells known as cardiomyocytes. These cells may have the potential to be injected into an ailing patients heart.

Harvesting stem cells from embryos is controversial, so there are guidelines created by the National Institutes of Health (NIH) that allow the public to understand what practices are not allowed.

Scientists can harvest perinatal stem cells from a variety of tissues, but the most common sources include:

The umbilical cord attaches a mother to her fetus. It is removed after birth and is a valuable source of stem cells. The blood it contains is rich in hematopoietic stem cells (HSC). It also contains smaller quantities of another cell type known as mesenchymal stem cells (MSCs).

The placenta is a large organ that acts as a connector between the mother and the fetus. Both placental blood and tissue are also rich in stem cells.

Finally, there is amniotic fluid surrounding a baby while it is in utero. It can be harvested if a pregnant woman needs a specialized kind of test known as amniocentesis. Both amniotic fluid and tissue contain stem cells, too.

Adult stem cells are usually harvested in one of three ways:

The blood draw, known as peripheral blood stem cell donation, extracts the stem cells directly from a donors bloodstream. The bone marrow stem cells come from deep within a bone often a flat bone such as the hip. Tissue fat is extracted from a fatty area, such as the waist.

Embryonic donations are harvested from fertilized human eggs that are less than five days old. The embryos are not grown within a mothers or surrogates womb, but instead, are multiplied in a laboratory. The embryos selected for harvesting stem cell are created within invitro fertilization clinics but are not selected for implantation.

Amniotic stem cells can be harvested at the same time that doctors use a needle to withdraw amniotic fluid during a pregnant womans amniocentesis. The same fluid, after being tested to ensure the babys health, can also be used to extract stem cells.

As mentioned, there is another source for stem cells the umbilical cord. Blood cells from the umbilical cord can be harvested after a babys birth. Cells can also be extracted from the postpartumhuman placenta, which is typically discarded as medical waste following childbirth.

The umbilical cord and the placenta are non-invasive sources of perinatal stem cells.

People who donate stem cells through the peripheral blood stem cell donor procedure report it to be a relativelypainless procedure. Similar to giving blood, the procedure takes about four hours. At a clinic or hospital, an able medical practitioner draws the blood from the donors vein in one of his arms using a needle injection. The technician sends the drawn blood into a machine, which extracts the stem cells. The blood is then returned to the donors body via a needle injected into the other arm. Some patients experience cramping or dizziness, but overall, its considered a painless procedure.

If a blood stem cell donor has a problem with his or her veins, a catheter may be injected in the neck or chest. The donor receives local anesthesia when a catheter-involved donation occurs.

During a bone marrow stem cell donor procedure, the donor is put under heavy sedation in an operating room. The hip is often the site chosen to harvest the bone marrow. More of the desired red marrow is found in flat bones, such as those in the pelvic region. The procedure takes up to two hours, with several extractions made while the patient is sedated. Although the procedure is painless due to sedation, recovery can take a couple of weeks.

Bone marrow stem cell donation takes a toll on the donorbecause it involves the extraction of up to 10 percent of the donors marrow. During the recovery period, the donors body gradually replenishes the marrow. Until that happens, the donor may feel fatigued and sore.

Some clinics offer regenerative and cosmetic therapies using the patients own stem cells derived from the fat tissue located on the sides of the waistline. Considered a simple procedure, clinics do this for therapeutic reasons or as a donation for research.

Stem cells differ from the trillions of other cells in your body. In fact, stem cells make up only a small fraction of the total cells in your body. Some people have a higher percentage of stem cells than others. But, stem cells are special because they are the mothers from which specialized cells grew and developed within us. When these cells divide, they become daughters. Some daughter cells simply self-replicate, while others form new kinds of cells altogether. This is the main way stem cells differ from other body cells they are the only ones capable of generating new cells.

The ways in which stem cells can directly treat patients grow each year. Regenerative medicine now relies heavily on stem cell applications. This type of treatment replaces diseased cells with new, healthy ones generated through donor stem cells. The donor can be another person or the patient themselves.

Sometimes, stem cells also exert therapeutic effects by traveling through the bloodstream to sites that need repair or by impacting their micro-environment through signaling mechanisms.

Some types of adult stem cells, like mesenchymal stem cells (MSCs), are well-known for exerting anti-inflammatory and anti-scarring effects. MSCs can also positively impact the immune system.

Conditions and diseases which stem cell regeneration therapy may help include Alzheimers disease, Parkinsons disease, and multiple sclerosis (MS). Heart disease, certain types of cancer, and stroke victims may also benefit in the future. Stem cell transplant promises advances in treatment for diabetes, spinal cord injury, severe burns, and osteoarthritis.

Researchers also utilize stem cells to test new drugs. In this case, an unhealthy tissue replicates into a larger sample. This method enables researchers to test various therapies on a diseased sample, rather than on an ailing patient.

Stem cell research also allows scientists to study how both healthy and diseased tissue grows and mutates under various conditions. They do this by harvesting stem cells from the heart, bones, and other body areas and studying them under intensive laboratory conditions. In this way, they get a better understanding of the human body, whether healthy or sick.

With the following stem cell transplant benefits, its not surprising people would like to try the therapy as another treatment option.

Physicians harvest stem cell from either the patient or a donor. For an autologous transplant, there is no risk of transferring any disease from another person. For an allogeneic transplant, the donor is meticulously screened before the therapy to make sure they are compatible with the patient and have healthy sources of stem cells.

One common and serious problem of transplants is the risk of rejecting the transplanted organs, tissues, stem cells, and others. With autologous stem cell therapy, the risk is avoided primarily because it comes from the same person.

Because stem cell transplants are typically done through infusion or injection, the complex and complicated surgical procedure is avoided. Theres no risk of accidental cuts and scarring post-surgery.

Recovery time from surgeries and other types of treatments is usually time-consuming. With stem cell therapy, it could only take about 3 months or less to get the patient back to their normal state.

As the number of stem cell treatments dramatically grew over the years, its survival rate also increased. A study published in the Journal of Clinical Oncology showed there was a significant increase in survival rate over 12 years among participants of the study. The study analyzed results from over 38,000 stem cell transplants on patients with blood cancers and other health conditions.

One hundred days following transplant, the researchers observed an improvement in the survival rate of patients with myeloid leukemia. The significant improvements we saw across all patient and disease populations should offer patients hope and, among physicians, reinforce the role of blood stem cell transplants as a curative option for life-threatening blood cancers and other diseases.

With the information above, people now have a better understanding of the answer to the question Where do stem cells come from? Stem cells are a broad topic to comprehend, and its better to go back to its basics to learn its mechanisms. This way, a person can have a piece of detailed knowledge about these master cells from a scientific perspective.

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

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Current Strategies and Challenges for Purification of …

By Dr. Matthew Watson

Theranostics 2017; 7(7):2067-2077. doi:10.7150/thno.19427

Review

Kiwon Ban1, Seongho Bae2, Young-sup Yoon2, 3

1. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong;2. Department of Medicine, Division of Cardiology, Emory University, Atlanta, Georgia, USA;3. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

Cardiomyocytes (CMs) derived from human pluripotent stem cells (hPSCs) are considered a most promising option for cell-based cardiac repair. Hence, various protocols have been developed for differentiating hPSCs into CMs. Despite remarkable improvement in the generation of hPSC-CMs, without purification, these protocols can only generate mixed cell populations including undifferentiated hPSCs or non-CMs, which may elicit adverse outcomes. Therefore, one of the major challenges for clinical use of hPSC-CMs is the development of efficient isolation techniques that allow enrichment of hPSC-CMs. In this review, we will discuss diverse strategies that have been developed to enrich hPSC-CMs. We will describe major characteristics of individual hPSC-CM purification methods including their scientific principles, advantages, limitations, and needed improvements. Development of a comprehensive system which can enrich hPSC-CMs will be ultimately useful for cell therapy for diseased hearts, human cardiac disease modeling, cardiac toxicity screening, and cardiac tissue engineering.

Keywords: Cardiomyocytes, hPSCs

Heart failure is the leading cause of death worldwide [1]. Approximately 6 million people suffer from heart failure in the United States every year [1]. Despite this high incidence, existing surgical and pharmacological interventions for treating heart failure are limited because these approaches only delay the progression of the disease; they cannot directly repair the damaged hearts [2]. In the case of large myocardial infarction (MI), patients progress to heart failure and die within short time from the onset of symptoms [3].

The adult human heart has minimal regenerative capacity, because during mammalian development, the proliferative capacity of cardiomyocytes (CMs) progressively diminishes and becomes terminally differentiated shortly after birth [4].Therefore, once CMs are damaged, they are rarely restored [5]. When MI occurs, the infarcted area is easily converted to non-contractile scar tissue due to loss of CMs and replacement by fibrosis [6]. Development of a fibroblastic scar initiates a series of events that lead to adverse remodeling, hypertrophy, and eventual heart failure [2, 3, 7].

While heart transplantation is considered the most viable option for treating advanced heart failure, the number of available donor hearts is always less than needed [6]. Therefore, more realistic therapeutic options have been required [2]. Accordingly, over the past two decades, cell-based cardiac repair has been intensively pursued [2, 7]. Several different cell types have been tested and varied outcomes were obtained. Indeed, the key factor for successful cell-based cardiac repair is to find the optimal cell type that can restore normal heart function. Naturally, CMs have been considered the best cell type to repair a damaged heart [8]. In fact, many scientists hypothesized that implanted CMs would survive in damaged hearts and form junctions with host CMs and synchronously contract with the host myocardium [9]. In fact, animal studies with primary fetal or neonatal CMs demonstrated that transplanted CMs could survive in infarcted hearts [9-11]. These primary CMs reduced scar size, increased wall thickness, and improved cardiac contractile function with signs of electro-mechanical integration [9-11]. These studies strongly suggest that CMs can be a promising source to repair the heart. However, the short supply and ethical concerns disallow using primary human CMs. In a patient with ischemic cardiomyopathy, about 40-50% of the CMs are lost in 40 to 60 grams of heart tissue [7]. Even if we seek to regenerate a fairly small portion of the damaged myocardium, a large number of human primary CMs would be required, which is impossible.

Accordingly, CMs differentiated from human pluripotent stem cells (hPSCs) including both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have emerged as a promising option for candidate CMs for cell therapy [12, 13]. hPSCs have many advantages as a source for CMs. First, hPSCs have obvious cardiomyogenic potential. hPSC derived-CMs (hPSC-CMs) possess a clear cardiac phenotype, displaying spontaneous contraction, cardiac excitation-contraction (EC) coupling, and expression of cardiac transcription factors, cardiac ion channels, and cardiac structural proteins [14, 15]. Second, undifferentiated hPSCs and their differentiated cardiac progeny display significant proliferation capacity, allowing generation of a large number of hPSC-CMs. Lastly, many pre-clinical studies demonstrated that implantation of hPSC-CMs can repair injured hearts and improve cardiac function [16-19]. Histologically, implanted hPSC-CMs are engrafted, aligned and coupled with the host CMs in a synchronized manner [16-19].

In the last two decades, various protocols for differentiating hPSCs into CMs have been developed to improve the efficiency, purity and clinical compatibility [20] [18]. The reported differentiation methods include, but are not limited to: differentiation via embryoid body (EB) formation [20], co-culture with END-2 cells [18], and monolayer culture [15, 21, 22]. The EB-mediated CM differentiation protocol is one of the most widely employed methods due to its simple procedure and low cost. However, it often becomes labor-intensive to produce scalable EBs for further differentiation, which makes it difficult for therapeutic applications. EB-mediated differentiation also produces inconsistent results, showing beating CMs from 5% to 70% of EBs. Recently, researchers developed monolayer methods to complement the problems of EB-based methods [15, 21, 22]. In one representative protocol, hPSCs are cultured at a high density (up to 80%) and treated with a high concentration of Activin A (100 ng/ml) for 1 day and BMP4 (10 ng/ml) for 4 days followed by continuous culture on regular RPMI media with B27 [15]. This protocol induces spontaneous beating at approximately 12 days and produces approximately 40% CMs after 3 weeks. These hPSC-CMs can be further cultured in RPMI-B27 medium for another 2-3 weeks without significant cell damage [15]. However, these protocols use media with proprietary formulations, which complicates clinical application. As shown, most monolayer-based methods employ B27, which is a complex mix of 21 components. Some of the components of B27, including bovine serum albumin (BSA), are animal-derived products, and the effects of B27 components on differentiation, maturation or subtype specification processes are poorly defined. In 2014, Burridge and his colleagues developed an advanced protocol that is defined, cost-effective and efficient [22]. By subtracting one component from B27 at a time and proceeding with cardiac differentiation, the researchers reported that BSA and L-ascorbic acid 2-phosphate are essential components in cardiac differentiation. Subsequently, by replacing BSA with rice-derived recombinant human albumin, the chemically defined medium with 3 components (CDM3) was produced. The application of a GSK-inhibitor, CHIR99021, for the first 2 days followed by 2 days of the Wnt-inhibitor Wnt-59 to cells is an optimal culture condition in CDM3 resulting in similar levels of live-cell yields and CM differentiation [22].

Despite remarkable improvement in the generation of hPSC-CMs, obtaining pure populations of hPSC-CMs still remains challenging. Currently available methods can only generate a mixture of cells which include not only CMs but other cell types. This is one of the most critical barriers for applications of hPSC-CMs in regenerative therapy, drug discovery, and disease investigation. For Instance, cardiac transplantation of non-pure hPSC-CMs mixed with undifferentiated hPSCs or other cell types may produce tumors or unwanted cell types in hearts [23-28]. Accordingly, a pure or enriched population of hPSC-CMs would be required, particularly for cardiac cell therapy. Enriched hPSC-CMs would also be more beneficial for myocardial repair due to improved electric and mechanical properties [29]. A pure, homogeneous population of hPSC-CMs would pose less arrhythmic risk and have enhanced contractile performance, and would be more useful in disease modeling as they better reflect native CM physiology. Finally, purified hPSC-CMs would better serve for testing drug efficacy and toxicity. Therefore, many researchers have tried to develop methods to purify CMs from cardiomyogenically differentiated hPSCs.

There are three important topics that are not addressed in this review. First is the beneficial role of other cell types such as endothelial cells and fibroblasts in the integration, survival, and function of CMs [30-32]. We did not discuss this issue because it would need a separate review due to the volume of material. While the roles of such cells are important, the value of having purified hPSC-CMs is not diminished. Although cell mixtures or tissue engineered products can be used, unless purified CMs are employed, they would form tumors or other cells/tissues when implanted in vivo. Our point here is that even if cardiomyocytes are mixed with non-CMs, all cells should be clearly defined and purified as well. If the mixture is made in a non-purified or non-defined manner (for example, an unsophisticated top-down approach), there would be undefined cells that are neither CMs, ECs, nor fibroblasts and these unidentified cells will make aberrant tissues or tumors. Second, we did not deal with maturation of hPSC-CMs because of its broad scope and depth [33, 34]. Third is direct reprogramming or conversion of somatic cells into CMs. There has been another advancement in the generation of CMs by directly reprogramming or converting somatic cells into CM-like cells by introducing a combination of cardiac transcription factors (TFs) or muscle-specific microRNAs (miRNAs) both in vitro and in vivo [35-41]. These cells are referred to as induced CMs (iCMs) or cardiac-like myocytes (iCLMs). While this is an important advancement, we did not cover this topic either due to its size. Accordingly, this review will focus on the various strategies for purifying or enriching hPSC-CMs reported to date (Figure 1).

Early on, researchers isolated hPSC-CMs manually under microscopy by mechanically separating out the beating areas from myogenically differentiating hPSC cultures [18, 20, 42]. This method usually generates 5-70% hPSC-CMs. Although generally crude, it can enrich even higher percentages of CMs with further culture. This manual isolation method has the advantage of being easy, but while it can be useful for small-scale research, it is very labor intensive and not scalable, precluding large scale research or clinical application.

Currently available strategies for enriching cardiomyocytes derived from human pluripotent stem cells.

Xu et el. reported that hPSC-CMs, due to their physical and structural properties, can be enriched by Percoll density gradient centrifugation [43]. Percoll was first formulated by Pertoft et al [44] and it was originally developed for the isolation of cells, organelles, or viruses by density centrifugation. The Percoll-based method has several advantages. The procedure for Percoll-based separation is very simple and easy, it is inexpensive, and its low viscosity allows more rapid sedimentation and lower centrifugal forces compared to a sucrose density gradient. Lastly, it can be prepared and kept for a long time in an isotonic solution to maintain osmolarity. Although Percoll separation has resulted in major improvements in hPSC-CM isolation procedures, it has clear limitations with regard to purity and scalability. Previous studies found that Percoll separation is only able to enrich 40 -70% of hPSC-CMs. It is also not compatible with large-scale enrichment of hPSC-CMs.

Another traditional method for purifying hPSC-CMs is based on the expression of a drug resistant gene or a fluorescent reporter gene such as eGFP or DsRed, which is driven by a cardiac specific promoter in genetically modified hPSC lines [45, 46]. Here, enrichment of hPSC-CMs can be achieved by either drug treatment to eliminate cells that do not express the drug resistant gene or with FACS to isolate fluorescent cells [47, 48].

Briefly, enrichment of PSC-CMs by genetically based selection was first reported by Klug et al [49]. The authors generated murine ES cell lines via permanent gene transfection of the aminoglycoside phosphotransferase gene driven by the MHC (MYH7) promoter. With this approach, highly purified murine ESC-CMs up to 99% were achieved. Next, several studies reported the use of various CM-specific promoters to enrich ESC-CMs such as Mhc (Myh6), Myh7, Ncx (Sodium Calcium exchanger) and Mlc2v (Myl2) [46, 50, 51]. In the case of hESCs, MHC/EGFP hESCs were generated by permanent transfection of the EGFP-tagged MHC promoter [52]. Similarly, an NKX2.5/eGFP hESC line was generated to enrich GFP positive CMs [53]. However, since MHC and NKX2.5 are expressed in general CMs, the resulting CMs contain a mixture of the three subtypes of CMs, nodal-, atrial-, and ventricular-like CMs. To enrich only ventricular-like CMs, Huber et al. generated MLC2v/GFP ESCs to be able to isolate MLC2v/GFP positive ventricular-like cells by FACS [52] [54-57]. In addition, the cGATA6 gene was used to purify nodal-like hESC-CMs [58]. Future studies should focus on testing new types of cardiac specific promoters and devising advanced selection procedures to improve this strategy.

While fluorescence-based cell sorting is more widely used, the drug selection method may be a better approach to enrich high purity of hPSC-CMs during differentiation/culture as it does not require FACS. The advantage is its capability for high-purity cell enrichment due to specific gene-based cell sorting. These highly pure cells can allow more precise mechanistic studies and disease modeling. Despite its many advantages, the primary weakness of genetic selection is genetic manipulation, which disallows its use for therapeutic application. Insertion of reporter genes into the host genome requires viral or nonviral transfection/transduction methods, which can induce mutagenesis and tumor formation [50, 59-61].

Practically, antibody-based cell enrichment is the best method for cell purification to date. When cell type-specific surface proteins or marker proteins are known, one can tag cells with antibodies against the proteins and sort the target cells by FACS or magnetic-activated cell sorting (MACS). The main advantage is its specificity and sensitivity, and its utility is well demonstrated in research and even in clinical therapy with hematopoietic cells [62]. Another advantage is that multiple surface markers can be used at the same time to isolate target cells when one marker is not sufficient. However, no studies have reported surface markers that are specific for CMs, even after many years. Recently, though, several researchers demonstrated that certain proteins can be useful for isolating hPSC-CMs.

In earlier studies, KDR (FLK1 or VEGFR2) and PDGFR- were used to isolate cardiac progenitor cells [63]. However, since these markers are also expressed on hematopoietic cells, endothelial cells, and smooth muscle cells, they could not enrich only hPSC-CMs. Next, two independent studies reported two surface proteins, SIRPA [64] and VCAM-1 [65], which it was claimed could specifically identify hPSC-CMs. Dubois et al. screened a panel of 370 known antibodies against CMs differentiated from hESCs and identified SIRPA as a specific surface protein expressed on hPSC-CMs [64]. FACS with anti-SIRPA antibody enabled the purification of CMs and cardiac precursors from cardiomyogenically differentiating hPSC cultures, producing cardiac troponin T (TNNT2, also known as cTNT)-positive cells, which are generally considered hPSC-CMs, with up to 98% purity. In addition, a study performed by Elliot and colleagues identified another cell surface marker, VCAM1 [53]. In this study, the authors used NKX2.5/eGFP hESCs to generate hPSC-CMs, allowing the cells to be sorted by their NKX2.5 expression. NKX2.5 is a well-known cardiac transcription factor and a specific marker for cardiac progenitor cells [66, 67]. To identify CM-specific surface proteins, the authors performed expression profiling analyses and found that expression levels of both VCAM1 and SIRPA were significantly upregulated in NKX2.5/eGFP+ cells. Flow cytometry results showed that both proteins were expressed on the cell surface of NKX2.5/eGFP+ cells. Differentiation day 14 NKX2.5/eGFP+ cells expressed VCAM1 (71 %) or SIRPA (85%) or both VCAM1 and SIRPA (37%). When the FACS-sorted SIRPA-VCAM1-, SIRPA+ or SIRPA+VCAM1+ cells were further cultured, only SIRPA+ or SIRPA+VCAM1+ cells showed NKX2.5/eGFP+ contracting portion. Of note, NKX2.5/eGFP and SIRPA positive cells showed higher expression of smooth muscle cell and endothelial cell markers indicating that cells sorted solely based on SIRPA expression may not be of pure cardiac lineage. Hence, the authors concluded that a more purified population of hPSC-CMs could be isolated by sorting with both cell surface markers. Despite significant improvements, it appears that these surface markers are not exclusively specific for CMs as these antibodies also mark other cell types including smooth muscle cells and endothelial cells. Furthermore, they are also known to be expressed in the brain and the lung, which raises concerns whether these surface proteins can be used as sole markers for the purification of hPSC-CMs compatible for clinical applications.

More recently, Protze et al. reported successful differentiation and enrichment of sinoatrial node-like pacemaker cells (SANLPCs) from differentiating hPSCs by using cell surface markers and an NKX2-5-reporter hPSC line [68]. They found that BMP signaling specified cardiac mesoderm toward the SANLPC fate and retinoic acid signaling enhanced the pacemaker phenotype. Furthermore, they showed that later inhibition of the FGF pathway, the TFG pathway, and the WNT pathway shifted cell fate into SANLPCs, and final cell sorting for SIRPA-positive and CD90-negative cells resulted in enrichment of SANLPCs up to ~83%. These SIRPA+CD90- cells showed the molecular, cellular and electrophysiological characteristics of SANLPCs [68]. While this study makes important progress in enriching SANLPCs by modulating signaling pathways, no specific surface markers for SANLPCs were identified and the yield was still short of what is usually expected for cells purified via FACS.

Hattori et al. developed a highly efficient non-genetic method for purifying hPSC-derived CMs, in which they employed a red fluorescent dye, tetramethylrhodamine methyl ester perchlorate (TMRM), that can label active mitochondria. Since CMs contain a large number of mitochondria, CMs from mice and marmosets (monkey) could be strongly stained with TMRM [69]. They further found that primary CMs from several different types of animals and CMs derived from both mESCs and hESCs were successfully purified by FACS up to 99% based on the TMRM signals. In addition to its efficiency for CM enrichment, TMRM did not affect cell viability and disappeared completely from the cells within 24 hrs. Importantly, injected hPSC-CMs purified in this way did not form teratoma in the heart tissues. However, since TMRM only functions in CMs with high mitochondrial density, this method cannot purify entire populations of hPSC-CMs [64]. While originally TMRM was claimed to be able to isolate mature hPSC-CMs, mounting evidence indicates that hPSC-CMs are similar to immature human CMs at embryonic or fetal stages. Therefore, both the exact phenotype of the cells isolated by TMRM and its utility are rather questionable [33, 34]. Two subsequent studies demonstrated that TMRM failed to accurately distinguish hPSC-CMs due to the insufficient amounts of mitochondria [64].

Employing the unique metabolic properties of CMs, Tohyama et al. developed an elegant purification method to enrich PSC-CMs [70]. This approach is based on the remarkable biochemical differences in lactate and glucose metabolism between CMs and non-CMs, including undifferentiated cells. Mammalian cells use glucose as their main energy source [71]. However, CMs are capable of energy production from different sources such as lactate or fatty acids [71]. A comparative transcriptome analysis was performed to detect metabolism-related genes which have different expression patterns between newborn mouse CMs and undifferentiated mouse ESCs. These results showed that CMs expressed genes encoding tricarboxylic acid (TCA) cycle enzymes more than genes related to lipid and amino acid synthesis and the pentose phosphate cycle compared to undifferentiated ESCs. To further prove this observation, they compared the metabolites of these pathways using fluxome analysis between CMs and other cell types such as ESCs, hepatocytes and skeletal muscle cells, and found that CMs have lower levels of metabolites related to lipid and amino acid synthesis and pentose phosphate. Subsequently, authors cultured newborn rat CMs and mouse ESCs in media with lactate, forcing the cells to use the TCA cycle instead of glucose, and they observed that CMs were the only cells to survive this condition for even 96 hrs. They further found that when PSC derivatives were cultured in lactate-supplemented and glucose-depleted culture medium, only CMs survived. Their yield of CM population was up to 99% and no tumors were formed when these CMs were transplanted into hearts. This lactate-based method has many advantages: its simple procedures, ease of application, no use of FACS for cell sorting, and relatively low cost. More recently, this method was applied to large-scale CM aggregates to ensure scalability. As a follow-up study, the same group recently reported a more refined lactate-based enrichment method which further depletes glutamine in addition to glucose [72]. The authors found that glutamine is essential for the survival of hPSCs since hPSCs are highly dependent on glycolysis for energy production rather than oxidative phosphorylation. The use of glutamine- and glucose-depleted lactate-containing media resulted in more highly purified hPSC-CMs with less than 0.001% of residual PSCs [72]. One concern of this lactate-based enrichment method is the health of the purified hPSC-CMs, because physiological and functional characteristics of hPSC-CMs cultured in glucose- and glutamine-depleted media for a long time may have functional impairment since CMs with mature mitochondria were not able to survive without glucose and glutamine, although they were able to use lactate to synthesize pyruvate and glutamate [72]. In addition, this lactate-based strategy can only be applied to hPSC- CMs, but not other hPSC derived cells such as neuron or -cells.

Our group also recently reported a new method to isolate hPSC-CMs by directly labelling cardiac specific mRNAs using nano-sized probes called molecular beacons (MBs) [29, 73, 74]. Designed to detect intracellular mRNA targets, MBs are dual-labeled antisense oligonucleotide (ODN) nano-scale probes with a DNA or RNA backbone, a Cy3 fluorophore at the 5' end, and a Black Hole quencher 2 (BHQ2) at the 3' end [75, 76]. They form a stem-loop (hairpin) structure in the absence of a complementary target, quenching the fluorescence of the reporter. Hybridization with the target mRNA opens the hairpin and physically separates the reporter from the quencher, allowing a fluorescence signal to be emitted upon excitation. The MB-based method can be applied to the purification of any cell type that has known specific gene(s) [77].

In one study [29], we designed five MBs targeting unique sites in TNNT2 or MYH6/7 mRNA in both mouse and human. To determine the most efficient transfection method to deliver MBs into living cells, various methods were tested and nucleofection was found to have the highest efficiency. Next, we tested the sensitivity and specificity of MBs using an immortalized mouse CM cell line, HL-1, and other cell types. Finally, we narrowed it down to one MB, MHC-MB, which showed >98% sensitivity and > 95% specificity. This MHC-MB was applied to cardiomyogenically differentiated mouse and human PSCs and FACS sorting was performed. The resultant MHC-MB-positive cells expressed cardiac proteins at ~97% when measured by flow cytometry. These sorted cells also demonstrated spontaneous contraction and all the molecular and electrophysiological signatures of human CMs. Importantly, when these purified CMs were injected into the mouse infarcted myocardium, they were well integrated into the myocardium without forming any tumors, and they improved cardiac function.

In a subsequent study [74], we refined a method to enrich ventricular CMs from differentiating PSCs (vCMs) by targeting a transcription factor which is not robustly expressed in cells. Since vCMs are the main source for generating cardiac contractile forces and the most frequently damaged in the heart, there has been great demand to develop a method that can obtain a pure population of vCMs for cardiac repair. Despite this critical unmet need, no studies have demonstrated the feasibility of isolating ventricular CMs without permanently altering their genome. Accordingly, we first designed MBs targeting the Iroquois homeobox protein 4 (Irx4) mRNA, a vCM specific transcription factor [78, 79]. After testing sensitivity and specificity, one IRX4-MB was selected and applied to myogenically differentiated mPSCs. The FACS-sorted IRX4-MB-positive cells exhibited vCM-like action potentials in more than 98% of cells when measured by several electrophysiological analyses including patch clamp and Ca2+ transient analyses. Furthermore, these cells maintained spontaneous contraction and expression of vCM-specific proteins.

The MB-based cell purification method is theoretically the most broadly applicable technology among the purification methods because it can isolate any target cells expressing any specific gene. Thus, the MB-based sorting technique can be applied to the isolation of other cell types such as neural-lineage cells or islet cells, which are critical elements in regenerative medicine but do not have specific surface proteins identified to date. In addition, theoretically, this technology may have the highest efficiency when MBs are designed to have the maximum sensitivity and specificity for the cells of interest, but not others. These characteristics are particularly important for cell therapy. Despite these advantages, the delivery method of MB into the cells needs to be improved. So far, nucleofection is the best delivery method, but caused some cell damage with < 70% cell viability. Thus, development of a safer delivery method will enable wider application of MB-based cell enrichment.

Recently, Miki and colleagues reported a novel method for purifying cells of interest based on endogenous miRNA activity [80]. Miki et al. employed several synthetic mRNA switches (= miRNA switch), which consist of synthetic mRNA sequences that include a recognition sequence for miRNA and an open reading frame that codes a desired gene, such as a regulatory protein that emits fluorescence or promotes cell death. If the miRNA recognition sequence binds to miRNA expressed in the desired cells, the expression of the regulatory protein is suppressed, thus distinguishing the cell type from others that do not contain the miRNA and express the protein.

Briefly, the authors first identified 109 miRNA candidates differentially expressed in distinct stages of hPSC-CMs (differentiation day 8 and 20). Next, they found that 14 miRNAs were co-expressed in hPSC-CMs at day 8 and day 20 and generated synthetic mRNAs that recognize these 14 miRNA, called miRNA switches. Among those miRNA switches, miR-1-, miR-208a-, and miR-499a-5p-switches successfully enriched hPSC-CMs with purity of sorted cells up to 96% determined by TNNT2 intracellular flow cytometry. Particularly, hPSC-CMs enriched by the miR-1-switch showed substantially higher expression of several cardiac specific genes/proteins and lower expression of non-CM genes/proteins compared with control cells. Patch clamp confirmed that these purified hPSC-CMs possessed both ventricular-like and atrial-like action potentials.

One of the major advantages of this technology is its wider applicability to other cell types. miRNA switches have the flexibility to design the open reading frame in the mRNA sequence such that any desired transgene can be incorporated into the miRNA switches to regulate the cell phenotype based on miRNA activity. The authors tested this possibility by incorporating BIM sequence, an apoptosis inducer, into the cardiac specific miR-1- and miR-208a switches and tested whether they could selectively induce apoptosis in non-CMs. They found that miR-1- and miR-208a-Bim-switches successfully enriched cTNT-positive hPSC-CMs without cell sorting. Enriched hPSC-CMs by 208a-Bim-switch were injected into the hearts of mice with acute MI and they engrafted, survived, expressed both cTNT and CX43, and formed gap junctions with the host myocardium. No teratoma was detected. In addition, other miRNA switches such as miR-126-, miR-122-5p-, and miR-375-switches targeting endothelial cells, hepatocytes, and -cells, respectively, successfully enriched these cell types differentiated from hPSCs. However, identification of specific miRNAs expressed only in the specific cell type of interest and verification of their specificity in target cells will be key issues for continuing to use this miRNA-based cell enrichment method.

Recent advances in biomedical engineering have contributed to developing systems that can isolate target cells using physicochemical properties of the cells. Microfluidic systems have been intensively applied for cell separation due to recent improvements in miniaturizing a cell culture system [81-83]. These advances made possible the design of automated microfluidic devices with cellular microenvironments and controlled fluid flows that save time and cost in experiments. Thus, there have been an increasing number of studies seeking to apply the microfluidic system for cell separation. Among the first, Singh et al. tested the possibility of using a microfluidic system for the separation of hPSC [84] by preparative detachment of hPSCs from differentiating cultures based on differences in the adhesion properties of different cell types. Distinct streams of buffer that generated varying levels of shear stress further allowed selective enrichment of hPSC colonies from mixed populations of adherent non-hPSCs, achieving up to 95% purity. Of note, this strategy produced hPSC survival rates almost two times higher than FACS, reaching 80%.

Subsequently, for hPSC-CMs purification, Xin et al. developed a microfluidic system with integrated ridge-like flow derivations and fishnet-like microcolumns for the enrichment of hiPSC-CMs [85]. This device is composed of a 250 mm-long microfluidic channel, which has two integrated parallel microcolumns with surfaces functionalized with anti-human TRA-1 antibody for undifferentiated hiPSC trapping. Aided by the ridge-like surface patterns on the upper wall of the channel, micro-streams are generated so that the cell suspension of mixed undifferentiated hiPSCs and hiPSC-CMs are forced to cross the functionalized fishnet-like microcolumns, resulting in trapping of undifferentiated hiPSCs due to the interaction between the hiPSCs and the columns, and the untrapped hiPSC-CMs are eventually separated. By modulating flow and coating with anti-human TRA-1 antibody, they were able to enrich CMs to more than 80% purity with 70% viability. While this study demonstrated that a microfluidic device could be used for purifying hPSC-CMs, it was not realistic because the authors used a mixture of only undifferentiated hiPSCs and hiPSC-CMs. In real cardiomyogenically differentiated hiPSCs, undifferentiated hiPSCs are rare and many intermediate stage cells or other cell types are present, so the idea that this simple device can select only hiPSC-CMs from a complex mixture is uncertain.

Overall, the advantages of microfluidic system based cell isolation include fast speed, improved cell viability and low cost owing to the automated microfluidic devices that can control cellular microenvironments and fluid flows [86-88]. However, microfluidic-based cell purification methods have limitations in terms of low purity and scalability [89-92]. In fact, there have been only a few studies demonstrating the feasibility that microfluidic device-based cell separation could achieve higher than 80% purity of target cells. Furthermore, currently available microfluidic devices allow only separation of a small number of cells (< 1011). To employ microfluidic devices for large-scale cell production, we need to develop a next generation of microfluidic devices that can achieve a throughput greater than 1011 sorted cells per hour with > 95% purity.

Having available a large quantity of a homogeneous population of cells of interest is an important factor in advancing biomedical research and clinical medicine, and is especially true for hPSC-CMs. While remarkable progress has been made in the methods for differentiating hPSCs into CMs, technologies to enrich hPSC-CMs, particularly those which are clinically applicable, have been emerging only over the last few years. Contamination with other cell types and even the heterogeneous nature of hPSC-CMs significantly hinder their use for several future applications such as cardiac drug toxicology screening, human cardiac disease modeling, and cell-based cardiac repair. For instance, cardiac drug-screening assays require pure populations of hPSC-CMs, so that the observed signals can be attributed to effects on human CMs. Studies of human cardiac diseases can also be more adequately interpreted with purified populations of patient derived hiPSC-CMs. Clinical applications with hPSC-CMs will need to be free of other PSC derivatives to minimize the risk of teratoma formation and other adverse outcomes.

Summary of representative methods for hPSC-CM purification

Schematic pictures of microfluidic device for enriching hiPSC-CMs. (A) The part of the device designed for trapping undifferentiated hiPSCs. (B) (Left) Illustration of the overall microfluidic device assembled with peristaltic pump, cell suspension reservoirs, and a serpentine channel. (Right) Magnified image showing a channel combining microcolumns and ridge-like flow derivation structures. Modified from Li et al. On chip purification of hiPSC-derived cardiomyocytes using a fishnet-like microstructure. Biofabrication. 2016 Sep 8;8(3): 035017

Therefore, development of reproducible, effective, non-mutagenic, scalable, and economical technologies for purifying hPSC-CMs, independent of hPSC lines or differentiation protocols, is a fundamental requirement for the success of hPSC-CM applications. Fortunately, new technologies based on the biological specificity of CMs such as MITO-tracker, molecular beacons, lactate-enriched-glucose depleted-media, and microRNA switches have been developed. In addition, technologies based on engineering principles have recently yielded a promising platform using microfluidic technology. While due to the short history of this field, more studies are needed to verify the utility of these technologies, the growing attention toward this research is a welcome move.

Another important question raised recently is how to non-genetically purify chamber-specific subtypes of CMs such as ventricular-like, atrial-like and nodal-like hPSC-CMs. So far, only a few studies have addressed this potential with human PSCs. We also showed that a molecular beacon-based strategy could enrich ventricular CMs differentiated from PSCs [74]. Another study demonstrated generation of SA-node like pacemaker cells by using a stepwise treatment of various morphogens and small molecules followed by cell sorting with several sub-specific surface markers. However, the yield of both studies was relatively low (<85%). Given the growing clinical importance of chamber-specific CMs, the strategies for purifying specific subtypes of CM that are independent of hPSC lines or differentiation protocols should be continuously developed. A recently reported cell surface capture-technology [93, 94] may facilitate identification of chamber specific CM proteins that will be useful for target CM isolation.

In summary, technological advances in the purification of hPSC-CMs have opened an avenue for realistic application of hPSC-CMs. Although initial success was achieved for purification of CMs from differentiating hPSC cultures, questions such as scalability, clinical compatibility, and cellular damage remain to be answered and isolation of human subtype CMs has yet to be demonstrated. While there are other challenges such as maturity, in vivo integration, and arrhythmogenecity, this development of purification technology represents major progress in the field and will provide unprecedented opportunities for cell-based therapy, disease modeling, drug discovery, and precision medicine. Furthermore, the availability of chamber-specific CMs with single cell analyses will facilitate more sophisticated investigation of human cardiac development and cardiac pathophysiology.

This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIP) (No 2015M3A9C6031514), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C2782, HI16C2211) and grants from NHLBI (R01HL127759, R01HL129511), NIDDK (DP3-DK108245). This work was also supported by a CityU Start-up Grant (No 7200492), a CityU Research Project (No 9610355), and a Georgia Immuno Engineering Consortium through funding from Georgia Institute of Technology, Emory University, and the Georgia Research Alliance.

The authors have declared that no competing interest exists.

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34. Robertson C, Tran DD, George SC. Concise review: maturation phases of human pluripotent stem cell-derived cardiomyocytes. Stem Cells. 2013;31:829-37

35. Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG. et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010;142:375-86

36. Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L. et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012;485:593-8

37. Jayawardena TM, Egemnazarov B, Finch EA, Zhang L, Payne JA, Pandya K. et al. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res. 2012;110:1465-73

38. Song K, Nam YJ, Luo X, Qi X, Tan W, Huang GN. et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature. 2012;485:599-604

39. Nam YJ, Song K, Luo X, Daniel E, Lambeth K, West K. et al. Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci U S A. 2013;110:5588-93

40. Jayawardena TM, Finch EA, Zhang L, Zhang H, Hodgkinson CP, Pratt RE. et al. MicroRNA induced cardiac reprogramming in vivo: Evidence for mature cardiac myocytes and improved cardiac function. Circ Res. 2015;116:418-24

41. Wada R, Muraoka N, Inagawa K, Yamakawa H, Miyamoto K, Sadahiro T. et al. Induction of human cardiomyocyte-like cells from fibroblasts by defined factors. Proc Natl Acad Sci U S A. 2013;110:12667-72

42. Caspi O, Huber I, Kehat I, Habib M, Arbel G, Gepstein A. et al. Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. J Am Coll Cardiol. 2007;50:1884-93

43. Xu C, Police S, Rao N, Carpenter MK. Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ Res. 2002;91:501-8

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Apple Stem Cells – The Anti-Aging skin care ingredient …

By Dr. Matthew Watson

What are Stem Cells?

Stem cells are super unique in that they have the ability to go through numerous cycles and cell divisions while maintaining the undifferentiated state. Primarily, stem cells are capable of self-renewal and can transform themselves into other cell types of the same tissue. Their crucial role is to replenish dying cells and regenerate damaged tissue. Stem cells have a limited life expectation due to environmental and intrinsic stress factors. Because their life is endangered by internal and external stresses, stem cells have to be protected and supported to delay preliminary aging. In aged bodies, the number and activity of stem cells in reduced.

Until several years ago, the tart, unappealing breed of the Swiss-grown Uttwiler Sptlauber apples, did not seem to offer anything of value. That was until Swiss scientists discovered the unusual longevity of the stem cells that kept these apples alive months after other apples shriveled and fell off their trees. In the rural region of Switzerland, home of these magical apples, it was discovered that when the unpicked apples or tree bark was punctured, Swiss Apple trees have the ability to heal themselves and last longer than other varieties. What was the secret to these apples prolonged lives?

Proven to Diminish the Signs of Aging

These scientists got to work to find out. What they revealed was that apple stem cells work just like human stem cells, they work to maintain and repair skin tissue. The main difference is that unlike apple stem cells, skin stem cells do not have a long lifespan, and once they begin depleting, the signs of aging start kicking in (in the forms of loose skin, wrinkles, the works). Time to harness these apple stem cells into anti aging skin care! Not so fast. As mentioned, Uttwiler Sptlauber apples are now very rare to the point that the extract can no longer be made in a traditional fashion. The great news is that scientists developed a plant cell culture technology, which involves breeding the apple stem cells in the laboratory.

Human stem cells on the skins epidermis are crucial to replenish the skin cells that are lost due to continual shedding. When epidermal stem cells are depleted, the number of lost or dying skin cells outpaces the production of new cells, threatening the skins health and appearance.

Like humans, plants also have stem cells. Enter the stem cells of the Uttwiler Sptlauber apple tree, whose fruit demonstrates an exceptionally long shelf-life. How can these promising stem cells help our skin?

Studies show that apple stem cells boosts production of human stem cells, protect the cell from stress, and decreases wrinkles. How does it work? The internal fluid of these plant cells contains components that help to protect and maintain human stem cells. Apple stem cells contain metabolites to ensure longevity as the tree is known for the fact that its fruit keep well over long periods of time.

When tested in vitro, the apple stem cell extract was applied to human stem cells from umbilical cords and was found to increase the number of the stem cells in culture. Furthermore, the addition of the ingredient to umbilical cord stem cells appeared to protect the cells from environmental stress such as UV light.

Apple stem cells do not have to be fed through the umbilical cord to benefit our skin! The extract derived from the plant cell culture technology is being harnessed as an active ingredient in anti aging skincare products. When delivered into the skin nanotechnology, the apple stem cells provide more dramatic results in decreasing lines, wrinkles, and environmental damage.

Currently referred to as The Fountain of Youth, intense research has proved that with just a concentration level of 0.1 % of the PhytoCellTec (apple stem cell extract) could proliferate a wealth of human stem cells by an astounding 80%! These wonder cells work super efficiently and are completely safe. Of the numerous benefits of apple stems cells, the most predominant include:

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Bone Marrow & Stem Cell Transplant | Weill Cornell Medicine

By Dr. Matthew Watson

Bone Marrow & Stem Cell Transplant

The Bone Marrow and Stem Cell Transplant Program at Weill Cornell Medicine was established with the mission of providing the best care and most innovative research in a compassionate and comfortable environment.

We take a multidisciplinary approach to care for patients with cancer and blood diseases who need stem cell transplants, providing world-class clinical care in collaboration with experts in leukemia, lymphoma, myeloma and other blood disorders. Based at NewYork-Presbyterian/Weill Cornell Medical Center, one of the top ten general hospitals in the nation, the expertise of our consulting team is unsurpassed.

Our patients and families cope with life-threatening illness; as such, sensitivity and compassion are a priority for our team. We view each patient as an individual, and our approach ensures that each treatment regimen is narrowly tailored to meet the unique, changing needs of our patients and their families before, during and after transplant.

As New Yorks premier healthcare institution, Weill Cornell Medicine is at the forefront of scientific research and clinical trials, enabling us to provide a full range of diagnostic and treatment protocols, including the latest breakthroughs in medicine.

Our Team

Our team of internationally-recognized bone marrow transplant and stem cell surgery specialists is known for advanced work and published research in:

Treating patients with aggressive leukemia and myelodysplastic syndromes

Bridge protocols for patients with refractory lymphoma and leukemia

Novel strategies to mobilize stem cells and improve transplantation for patients with multiple myeloma, leukemia and lymphoma

Transplants for solid tumors, severe auto-immune disorders, and AIDS

Treatment

We pride ourselves on exceptional outcomes and offer patients the most advanced diagnostic methods and treatment therapies to improve quality of life, including:

Umbilical cord blood transplant

Outpatient transplant

Autologous stem cell transplant; uses stem cells extracted from the bone marrow or peripheral blood of the patients own blood

Allogeneic stem cell transplant; uses stem cells extracted from the bone marrow or peripheral blood of a matching donor

Hematopoietic stem cell transplant; used to treat certain cancers of the blood/bone marrow, including leukemia and myeloma

Matched unrelated donor stem cell transplantation through the National Donor Matching Program

Non-ablative "mini" transplants

Haplo-Cord Transplant, allowing us to find donors for all patients, regardless of age or ethnic background

Bendamustine, a therapy that is well-tolerated and has excellent response rates in patients with myeloma

Novel forms of transplant, offering hope and success to older patients with leukemia

Clinical Trials

Clinical trials are important to improve outcomes and offer new treatment options. At Weill Cornell Medicine, we conduct more studies in blood cancers than any of our regional peers, allowing us to provide our patients with access to many multi-phase clinical trials. As active members of the international cancer research community, our oncologists also collaborate with other research centers to offer patients the most promising treatments available.

Second Opinions

In concert with your referring physician, we are always available to offer a second opinion in the form of a consultation with one of our specialists.

Why Choose Us?

Our collaborative approach means our patients receive supportive, comprehensive care and the most cutting-edge stem cell therapy and treatments. This enables patients to receive the best possible transplant outcomes. Additionally, we offer more allogeneic stem cell transplants for older adults than any other center in New York City and the entire tri-state area.

For more information or to schedule an appointment, call us at 212-746-2119 or 212-746-2646.

Located in New York City, Weill Cornell Medical College is ranked among the nations best by U.S. News & World Report year after year.

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What is BMC, Bone Marrow Stem Cell Therapy?

By Dr. Matthew Watson

Bone Marrow Concentrate (BMC) Therapy, also known as Bone Marrow Aspirate Concentrate (BMAC) Therapy, is a promising cutting-edge regenerative therapy to help accelerate healing in moderate to severe osteoarthritis and tendon injuries. While similar to Platelet Rich Plasma (PRP) in its ability to harness the bodys ability to heal itself through the aid of growth factors, BMC also utilizes regenerative cells that are contained within a patients own bone marrow. The marrow contains a rich reservoir of pluripotent stem cells that can be withdrawn from the patients hip bone and used for the procedure. Unlike other cells of the body, stem cells are undifferentiated, meaning they are able to replicate themselves into various types of tissue.

In the past, the process of removing and harvesting these cells was often difficult and expensive. With recent medical advancements in both the aspiration of the bone marrow and harvesting of the regenerative cells, the procedure can be done with minimal discomfort and patients are sent home the same day. The process is relatively simple. The patient is first numbed using a mixture of local anesthetics. Under the guidance of an X-Ray machine, the physician then removes a small amount of the patients bone marrow from the hip bone which is then placed into a centrifuge to separate the regenerative cells and platelets from the rest of the blood products. The final product is a concentrate which has approximately 5-10 times the baseline levels of regenerative cells and growth factors. This point of care treatment allows for minimal manipulation of cells which are then injected to the injured area. The entire process takes approximately 2 hours and patients go home the same day.

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Stem Cell Therapy Has a Lot to OfferIt Just May Take Some …

By Dr. Matthew Watson

Stem Cell Therapy Has a Lot to OfferIt Just May Take Some Time to Get There

By: Ashwini Nagappan

In conversation with the New York Times, Dr. Shinya Yamanaka, the director of Kyoto Universitys Center for iPS Cell Research and Application and researcher at the Gladstone Institutes, illuminates the complexities and future of stem-cell research. Yamanaka was jointly awarded the 2012 Nobel Prize in Physiology or Medicine for reconfiguring adult cells back to their pluripotent states. These induced pluripotent stem cells, or iPS cells, have been used as treatments for conditions such as macular degeneration.

However, Yamanaka mentions that these treatments are temporarily suspended because of the possibility of mutations developing in the patients iPS cells. Cancer could be a potential outcome because the production of iPS cells increases the chance of mutations. Researchers are rigorously testing to make sure that there are no cancer-causing mutations and that the cells function as they should. In order to be certain that these cells are safe, they are transplantedinto mice or rats for about a year. Yamanaka approximates that only 100 lines would be needed to cover the Japanese population and 200 lines for the US population.

Yamanaka acknowledges that the potentialfor stem cells may have been too eagerlyanticipated as they can only remedy the small portion of diseases that are caused by a single cell failure such as heart failure. Stem cell therapy cannot target diseases caused by multiple types of cell failures. He mentions an alternative to iPS known as direct cellular reprogramming, which would be beneficial if the patient in question was elderly instead of a younger person, and if the area targeted was larger instead of a small wound.

In essence, Yamanaka highlights the need for an ethical consensus in order to understand how to move forward with advancing stem cell technology. Further, iPS cells are fairly young they are only tenyears old. For patients to be able to receive these treatments requires money and time. In the mean time, Yamanaka recommends arrivingat an ethical consensus onthe use of stem cells.

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Spinal Neurons Grown From Stem Cells For First Time | News …

By Dr. Matthew Watson

Modern medicine has still not managed to crack the problem of spinal cord injuries that result in significant paralysis or loss of functional status.

There are numerous factors that influence the inability to restore movement or autonomous bodily control to these patients. A prominent example of these is the inability to cultivate new neurons that make up and power the spinal cord.

However, some researchers have claimed that they have successfully induced generic human stem cells to differentiate into stem cells that apply more specifically to the spine.

Why We Cant Repair a Spine (Yet)

Strategies involving the implantation of any kind of donor cell to regenerate or recreate damaged spinal tissue have not shown much success. Furthermore, some medical researchers also believe that such forays into regenerative medicine are not feasible, in terms of costs and resources, at this point. Therefore, this area of cell-based therapy is still very much at the development stage.

The goals of many current projects in this area revolve around the restoration of the motor function in subjects (mostly rodents in animal models). This requires the full re-generation and reinstatement of the corticospinal tract (CST), an important spinal region that communicates with the relevant cortices in the brain.

A limited number of reports claim to have achieved this. However, this leaves the rest of the spine un-addressed, which may have a residual effect on movement and other functions.

New Direction in Cell-Based Therapy for Spinal Injuries

In the past, CST-based trials used grafts of multipotent cells, which were progenitor cells rather than true stem cells.

However, a newer study has documented a technique in which human pluripotent stem cells were used, which could differentiate into all the cells a spinal section needs, and not just the CST ones.

Reportedly, these neural stem cells further diversified into different types of neurons. Therefore, it can be concluded that neural stem cells may be capable of more complete regeneration of missing or damaged spinal tissue in living subjects.

The researchers behind the apparent breakthrough claimed that their cells were capable of doing this in an appropriate model. However, the research was conducted by causing the stem cells to grow a customized spinal graft, which was then transplanted using the model.

A transverse spinal section showing some functions of various spinal region. (Source: Public Domain)

The scientists claimed that these grafts integrated well with the sections of pre-existing spinal tissue upstream and downstream of the graft location. These consisted of various intra-, supra- and cortico-spinal networks of neural connections, which allowed peripheral nervous functions, including movement, under normal circumstances.

In addition, it is necessary for these networks to distinguish between the dorsal (or backward-facing) and ventral portions of the spine. This is because these regions send different signals to the brain in different directions in the average healthy spine. The researchers asserted that their spinal grafts were indeed capable of these distinctions.

The scientists behind this project reported that their models subjects gained increased functional status as a result of receiving one of these grafts. However, it can be assumed that these assertions are getting slightly ahead of their time, in terms of being approved as a real-world treatment.

The researchers also noted that their new spinal stem cells and the neurons that they differentiate into can be used as an excellent in vitro model for the neurobiology of the spine. In addition, the cells may also now be used to test other novel potential treatments for spinal disorders.

Highlights

The scientists behind this project collaborated across the departments of neurosciences and psychiatry & neurology at the University of California (Los Angeles), as well as the San Diego Veterans Administrations Healthcare System. The team published their findings in an August 2018 issue of Nature Methods.

The researchers also hope that future work on this model could lead to the application of their cells to next-generation regenerative medicine that focuses on the spine and how to repair it after injury or damage.

Therefore, we may be able to look forward to a time, in which improved medicine could restore paraplegic patients to the health and autonomy that they may cherish.

Top Image: The spine is an important component of the human nervous system. (Source: Pixabay)

References

H. Kumamaru, et al. (2018) Generation and post-injury integration of human spinal cord neural stem cells. Nature Methods.

S. A. Goldman. (2016) Stem and Progenitor Cell-Based Therapy of the Central Nervous System: Hopes, Hype, and Wishful Thinking. Cell Stem Cell. 18:(2). pp.174-188.

K. Kadoya, et al. (2016) Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med. 22:(5). pp.479-487.

Deirdre ODonnell

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Regenerative Stem Cell Therapy | Treatment for Back Pain | VSI

By Dr. Matthew Watson

share WHAT ARE STEM CELLS?

Mesenchymal stem cells are specialized cells that naturally grow in our body and can differentiate into bone, cartilage or fat cells. They are widely used in medicine as a natural healing solution to effectively treat orthopedic conditions including the spine and major joints (like the shoulder, hip, knee, ankle, etc.).

There are many benefits of stem cell therapy, including but not limited to:

The human body has multiple sites for stem cells to repair degenerated and injured structures. We have found that obtaining stem cells from the hip bone (iliac bone) is easily performed within minutes. After the stem cells are obtained, minutes later they can be used for treatment in our outpatient state-of-the-art-facility. Regenerative stem cell injections are performed using image guidance (i.e. ultrasound or fluoroscopy) to ensure accurate placement of the stem cells. Once the affected area is sterilized and numbed with a novocaine-type solution, stem cells are injected and begin regenerating and strengthening weakened joints.

Stem cell injections are most commonly used for treatment of the following conditions:

Stem cell injections are designed to heal and strengthen damaged tissue, therefore pain relief is typically noticed several weeks after the procedure. Final relief is seen approximately two to three months after the entire treatment protocol has been completed.

In most cases, patients respond very well to just one treatment. Some patients, depending on the severity of the injury, may benefit from two to three injections over the course of 12 months.

As with all procedures, there are minor risks associated with stem cell injections including infection, bleeding, or nerve damage. It is important to note that there is no risk of allergic reaction since you are using your bodys own healing factors. The physicians at Virginia Spine Institute will always recommend the safest and most efficient procedures for our patients, however, your physician will review any possible risks associated with this treatment prior to administering.

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How Bone Marrow and Stem Cells are Collected | BMT Infonet

By Dr. Matthew Watson

Language English

If you are providing the blood stem cells for a transplant, they will either be collected from your bloodstream (peripheral blood) or from your bone marrow.

The largest concentration of blood stem cells is in your bone marrow. However, the blood stem cells can be moved or "mobilized" out of the bone marrow into the bloodstream (peripheral blood) where they can be easily collected. Most transplants these days use stem cells collected from the bloodstream.

When blood stem cells are collected from the bloodstream, the procedure is called a peripheral blood stem cell collection or harvest.

Prior to the harvest, you will receive injections of a drug such as filgrastim (Neupogen) or plerixifor (Mozobil) over a four to five day period. These drugs move stem cells out of the bone marrow into the bloodstream.

Most people tolerate these drugs well, although mild, flu-like symptoms are common. The symptoms end a few days after the injections stop.

If you are collecting stem cells for your own transplant, chemotherapy drugs may be used to help move the stem cells out of your bone marrow into the bloodstream.

Peripheral blood stem cell collections are done in an outpatient clinic.

The procedure is painless. However, you may feel lightheaded, cold or numb around the lips. Some people feel cramping in their hands which is caused by the blood thinning agent used during the procedure. These symptoms cease when the procedure ends.

The procedure used to collect bone marrow for transplant is called a bone marrow harvest. It is a surgical procedure that takes place in a hospital operating room. Typically it is done as an outpatient procedure.

The amount of bone marrow harvested depends on the size of the patient and the concentration of blood stem cells in your marrow.

Typically one to two quarts of marrow and blood are harvested. While this may sound like a lot, your body can usually replace it in four weeks.

When the anesthesia wears off, you may feel some discomfort in your hip and lower back for several days. The pain is similar to what you would feel if you took a hard fall and bruised your hip. You may find sitting for a long period of time or climbing stairs uncomfortable for a few days. The pain is usually relieved with acetaminophen (Tylenol).

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Stem Cell Transplants in Cancer Treatment – National …

By Dr. Matthew Watson

Stem cell transplants are procedures that restore blood-forming stem cells in people who have had theirs destroyed by the very high doses of chemotherapy or radiation therapy that are used to treat certain cancers.

Blood-forming stem cells are important because they grow into different types of blood cells. The main types of blood cells are:

You need all three types of blood cells to be healthy.

In a stem cell transplant, you receive healthy blood-forming stem cells through a needle in your vein. Once they enter your bloodstream, the stem cells travel to the bone marrow, where they take the place of the cells that were destroyed by treatment. The blood-forming stem cells that are used in transplants can come from the bone marrow, bloodstream, or umbilical cord. Transplants can be:

To reduce possible side effects and improve the chances that an allogeneic transplant will work, the donors blood-forming stem cells must match yours in certain ways. To learn more about how blood-forming stem cells are matched, see Blood-Forming Stem Cell Transplants.

Stem cell transplants do not usually work against cancer directly. Instead, they help you recover your ability to produce stem cells after treatment with very high doses of radiation therapy, chemotherapy, or both.

However, in multiple myeloma and some types of leukemia, the stem cell transplant may work against cancer directly. This happens because of an effect called graft-versus-tumor that can occur after allogeneic transplants. Graft-versus-tumor occurs when white blood cells from your donor (the graft) attack any cancer cells that remain in your body (the tumor) after high-dose treatments. This effect improves the success of the treatments.

Stem cell transplants are most often used to help people with leukemia and lymphoma. They may also be used for neuroblastoma and multiple myeloma.

Stem cell transplants for other types of cancer are being studied in clinical trials, which are research studies involving people. To find a study that may be an option for you, see Find a Clinical Trial.

The high doses of cancer treatment that you have before a stem cell transplant can cause problems such as bleeding and an increased risk of infection. Talk with your doctor or nurse about other side effects that you might have and how serious they might be. For more information about side effects and how to manage them, see the section on side effects.

If you have an allogeneic transplant, you might develop a serious problem called graft-versus-host disease. Graft-versus-host disease can occur when white blood cells from your donor (the graft) recognize cells in your body (the host) as foreign and attack them. This problem can cause damage to your skin, liver, intestines, and many other organs. It can occur a few weeks after the transplant or much later. Graft-versus-host disease can be treated with steroids or other drugs that suppress your immune system.

The closer your donors blood-forming stem cells match yours, the less likely you are to have graft-versus-host disease. Your doctor may also try to prevent it by giving you drugs to suppress your immune system.

Stem cells transplants are complicated procedures that are very expensive. Most insurance plans cover some of the costs of transplants for certain types of cancer. Talk with your health plan about which services it will pay for. Talking with the business office where you go for treatment may help you understand all the costs involved.

To learn about groups that may be able to provide financial help, go to the National Cancer Institute database, Organizations that Offer Support Services and search "financial assistance." Or call toll-free 1-800-4-CANCER (1-800-422-6237) for information about groups that may be able to help.

When you need an allogeneic stem cell transplant, you will need to go to a hospital that has a specialized transplant center. The National Marrow Donor Program maintains a list of transplant centers in the United States that can help you find a transplant center.

Unless you live near a transplant center, you may need to travel from home for your treatment. You might need to stay in the hospital during your transplant, you may be able to have it as an outpatient, or you may need to be in the hospital only part of the time. When you are not in the hospital, you will need to stay in a hotel or apartment nearby. Many transplant centers can assist with finding nearby housing.

A stem cell transplant can take a few months to complete. The process begins with treatment of high doses of chemotherapy, radiation therapy, or a combination of the two. This treatment goes on for a week or two. Once you have finished, you will have a few days to rest.

Next, you will receive the blood-forming stem cells. The stem cells will be given to you through an IV catheter. This process is like receiving a blood transfusion. It takes 1 to 5 hours to receive all the stem cells.

After receiving the stem cells, you begin the recovery phase. During this time, you wait for the blood cells you received to start making new blood cells.

Even after your blood counts return to normal, it takes much longer for your immune system to fully recoverseveral months for autologous transplants and 1 to 2 years for allogeneic or syngeneic transplants.

Stem cell transplants affect people in different ways. How you feel depends on:

Since people respond to stem cell transplants in different ways, your doctor or nurses cannot know for sure how the procedure will make you feel.

Doctors will follow the progress of the new blood cells by checking your blood counts often. As the newly transplanted stem cells produce blood cells, your blood counts will go up.

The high-dose treatments that you have before a stem cell transplant can cause side effects that make it hard to eat, such as mouth sores and nausea. Tell your doctor or nurse if you have trouble eating while you are receiving treatment. You might also find it helpful to speak with a dietitian. For more information about coping with eating problems see the booklet Eating Hints or the section on side effects.

Whether or not you can work during a stem cell transplant may depend on the type of job you have. The process of a stem cell transplant, with the high-dose treatments, the transplant, and recovery, can take weeks or months. You will be in and out of the hospital during this time. Even when you are not in the hospital, sometimes you will need to stay near it, rather than staying in your own home. So, if your job allows, you may want to arrange to work remotely part-time.

Many employers are required by law to change your work schedule to meet your needs during cancer treatment. Talk with your employer about ways to adjust your work during treatment. You can learn more about these laws by talking with a social worker.

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Stem Cell Transplants in Cancer Treatment - National ...

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What is VetStem Regenerative Medicine? | Why Use Adipose …

By Dr. Matthew Watson

VetStem Technology: Summary

VetStem Regenerative Cell Therapy is based on a clinical technology licensed from Artecel Inc. Original patents are from the University of Pittsburgh and Duke University.

Adipose-derived regenerative cells are:

VetStem Regenerative Cell (VSRC) therapy delivers a functionally diverse cell population able to communicate with other cells in their local environment. Until recently, differentiation was thought to be the primary function of regenerative cells. However, the functions of regenerative cells are now known to be much more diverse and are implicated in a highly integrated and complex network. VSRC therapy should be viewed as a complex, yet balanced, approach to a therapeutic goal. Unlike traditional medicine, in which one drug targets one receptor, Regenerative Medicine, including VSRC therapy, can be applied in a wide variety of traumatic and developmental diseases. Regenerative cell functions include:

In general, in vitro studies demonstrate that MSCs limit inflammatory responses and promote anti-inflammatory pathways.

Multiple studies demonstrate that MSCs secrete bioactive levels of cytokines and growth factors that support angiogenesis, tissue remodeling, differentiation, and antiapoptotic events.25,28 MSCs secrete a number of angiogenesis-related cytokines such as:28

Adipose-derived MSC studies demonstrate a diverse plasticity, including differentiation into adipo-, osteo-, chondro-, myo-, cardiomyo-, endothelial, hepato-, neuro-, epithelial, and hematopoietic lineages, similar to that described for bone marrow derived MSCs.22 These data are supported by in vivo experiments and functional studies that demonstrated the regenerative capacity of adipose-derived MSCs to repair damaged or diseased tissue via transplant engraftment and differentiation.6,9,30

Homing (chemotaxis) is an event by which a cell migrates from one area of the body to a distant site where it may be needed for a given physiological event. Homing is an important function of MSCs and other progenitor cells and one mechanism by which intravenous or parenteral administration of MSCs permits an auto-transplanted therapeutic cell to effectively target a specific area of pathology.

Adipose-derived regenerative cells contain endothelial progenitor cells and MSCs that assist in angiogenesis and neovascularization by the secretion of cytokines, such as hepatic growth factor (HGF), vascular endothelial growth factor (VEGF), placental growth factor (PGF), transforming growth factor (TGF), fibroblast growth factor (FGF-2), and angiopoietin.25

Apoptosis is defined as a programmed cell death or cell suicide, an event that is genetically controlled.35 Under normal conditions, apoptosis determines the lifespan and coordinated removal of cells. Unlike during necrosis, apoptotic cells are typically intact during their removal (phagocytosis).

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Stem cell-filled implant restores some spinal cord …

By Dr. Matthew Watson

Stem cell-filled implants helped repair spinal cord damage in animals, according to a study led by UC San Diego scientists. If all goes well, the implants with neural stem cells could be ready for testing in human patients in a few years.

Rats with completely severed spinal cords regained some voluntary motion after getting the implants, said the study, published Monday in the journal Nature Medicine. The study is online at j.mp/ucsdspine.

They were able to move the joints of their lower legs, said study co-author Dr. Mark Tuszynski. They couldn't support their weight very well, but they could move the legs around the joints. If one were to project what this means to humans, it might mean that the legs are still weak, but that with an assist they would be able to control them.

The next step is to repeat the procedure in monkeys, said Tuszynski, director of the Translational Neuroscience Institute at UC San Diego School of Medicine.

If successful, it would fulfill one of the biggest hopes for stem cell therapy.

Repairing spinal cord injuries has long been a major goal of the states stem cell program, the California Institute for Regenerative Medicine, or CIRM. The agency was formed in 2004 with the passage of Prop. 71. The late actor Christopher Reeve figured prominently in the campaign for Prop. 71.

While there have been encouraging reports of individual spinal cord injury patients benefiting from stem cell-based therapy, no such treatment has been approved as safe and effective. So scientists at UCSD and elsewhere are trying to make a treatment that can be reliably replicated.

Another study with neural stem cells without the implant has shown benefit in monkeys after spinal cord injury, Tuszynski said. This work is closer to the clinical stage.

The rat implants were constructed by 3D bioprinting of a biologically compatible hydrogel, which is mostly made up of water. These 2-millimeter-wide implants contain tiny channels that guide growth of neural stem cells, also called neural progenitor cells. The cells matured into neurons and reconnected severed nerves, Tuszynski said.

Besides guiding growth, the implants allowed blood vessels to grow, nourishing the newly formed cells. This process, called vascularization, has been hard to achieve in growing new tissue. But with the biologically compatible implants, vascularization occurred spontaneously.

The implants also protected the neural stem cells from the inflammatory damage associated with a fresh injury.

This is a nice marriage of the technology of bioengineering and 3D printing with stem cell biology to treat a really important human disease that needs better therapy, Tuszynski said.

Implants can be quickly custom-made for human spinal cord injuries, according to the study. Researchers bioprinted implants of 4 centimeters within 10 minutes. These were made according to MRI scans of real human spinal cord injuries.

Two other UCSD study authors, Shaochen Chen and Wei Zhu, have co-founded a San Diego startup, Allegro 3D, to commercialize the rapid bioprinting technology. Allegro is doing this independently of the spinal cord injury research.

We will be talking to people to find a partner, said Chen, a founding co-director of the Biomaterials and Tissue Engineering Center at UC San Diego. It takes money, time and effort, so it won't be done in a university setting.

The neural stem cells are produced from a lineage of human embryonic stem cells. This lineage was one of the original certified while George W. Bush was president.

The researchers treat the cells with their own cocktail of growth chemicals that coax them into becoming spinal cord neural stem cells, which cant become any other kind of cell besides types of spinal cord cells.

When these cells are placed at the injury site, with or without the implant, the stem cells complete development.

Importantly, these cells grow axons, the long fibers that carry nerve signals, Tuszynski said. They extend out of the implant and into the spinal cord below the injury. They relay signals that cross synapses, the tiny gaps between nerve cells.

Because the cells arent from the patient, the body may tend to reject them. So patients receiving these cells will need immunosuppressive therapy, he said.

Newer classes of immune-suppressing drugs now available are safer and better tolerated than earlier ones, Tusyznski said.

We think patients would stay on them for awhile, he said.

The research was funded by the National Institutes of Health; the California Institute for Regenerative Medicine; and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

UCSD also hosts ongoing stem cell-based clinical trials for spinal cord injuries and other diseases. More information can be found at the Sanford Stem Cell Clinical Center, reachable at j.mp/ucsdssc.

Related reading

3D printed implant promotes nerve cell growth to treat spinal cord injury

Biomimetic 3D-printed scaffolds for spinal cord injury repair

Allegro 3D

Stem cell-based spinal cord therapy expanded to more patients

Stem cells have become keys to unlock how life develops

UCSD finds possible treatment for paralysis

Genetic analysis conducted on one Neanderthal woman who lived 52,000 years ago was published Oct. 5 in a report in the journal Science. (October 6, 2017)

Genetic analysis conducted on one Neanderthal woman who lived 52,000 years ago was published Oct. 5 in a report in the journal Science. (October 6, 2017)

At 9:52 a.m. Pacific, OSIRIS-REx (short for Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer) hits its closest point to Earth, 11,000 miles above Antarctica. (Sept. 22, 2017)

At 9:52 a.m. Pacific, OSIRIS-REx (short for Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer) hits its closest point to Earth, 11,000 miles above Antarctica. (Sept. 22, 2017)

The Food and Drug Administration has launched a crackdown on clinics hawking stem cell treatments for a range of ailments. (September 1, 2017) (Sign up for our free video newsletter here http://bit.ly/2n6VKPR)

The Food and Drug Administration has launched a crackdown on clinics hawking stem cell treatments for a range of ailments. (September 1, 2017) (Sign up for our free video newsletter here http://bit.ly/2n6VKPR)

Researchers used eggs from healthy females and the sperm of a man who carried a gene mutation that causes inherited hypertrophic cardiomyopathy. (Aug. 3, 2017)(Sign up for our free video newsletter here http://bit.ly/2n6VKPR)

Researchers used eggs from healthy females and the sperm of a man who carried a gene mutation that causes inherited hypertrophic cardiomyopathy. (Aug. 3, 2017)(Sign up for our free video newsletter here http://bit.ly/2n6VKPR)

Research published July 27 suggested that transcranial magnetic stimulation could prove useful in distinguishing Alzheimers disease from frontotemporal dementia. (July 27, 2017)(Sign up for our free video newsletter here http://bit.ly/2n6VKPR)

Research published July 27 suggested that transcranial magnetic stimulation could prove useful in distinguishing Alzheimers disease from frontotemporal dementia. (July 27, 2017)(Sign up for our free video newsletter here http://bit.ly/2n6VKPR)

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