A bone marrow transplant is a medical treatment that replaces your bone marrow with healthy bone marrow stem cells. It is also called a stem cell transplant or, more specifically, a hematopoietic stem cell transplant. This type of transplantation can treat certain types of cancer and other diseases that affect the bone marrow. Like any cancer treatment, it can cause side effects. These side effects can be different for everyone and depend on the type of transplant you receive, your general health, and other factors.

It is a good idea to talk with your health care team about the possible side effects before starting your transplant process. This includes short-term side effects that are expected to go away over time, as well as side effects that may occur later, last longer, or be permanent. This will help you feel more prepared and supported if a side effect does occur.

And, talk with your health care team regularly about any symptoms or side effects you experience throughout your transplantation process and recovery. This includes when a side effect worsens or a new problem appears. Managing side effects is an important part of cancer care and treatment and it is especially important during transplantation. This type of care is called palliative or supportive care. It can help people with any stage of cancer feel better.

There are different kinds of bone marrow transplants and the side effects can be different. The side effects for an autologous transplant and an allogenic transplant are detailed below.

An autologous bone marrow transplant is also called an AUTO transplant or stem cell rescue. During an AUTO transplant, your own stem cells are removed from your body before an intensive chemotherapy treatment. This intensive treatment, which can also include radiation therapy, damages your stem cells. The healthy stem cells are then put back in your body to "replace" the ones damaged by the treatment.

Many side effects of an AUTO transplant are similar to common side effects of chemotherapy and radiation therapy. The most serious side effect is a higher risk of infection from your body's low levels of white blood cells.

Infection. Chemotherapy and some other treatments weaken your body's infection-fighting system, called the immune system. This is especially true of treatment given for a bone marrow/stem cell transplant, because the bone marrow is part of the immune system. When your immune system is weakened, your body cannot protect itself as well against germs. Most of these germs already live in your body. When your immune system is strong, these germs do not make you sick. But after a transplant, they can cause an infection. Fortunately, most of these infections can be easily treated with antibiotics.

About 2 weeks after your transplant day, your immune system will begin to recover. You have the highest risk of infections in the first few weeks after transplant, but you will still be at a higher risk of infections for a year or more after. Your health care team will talk to you about ways to reduce your risk of infections during your recovery. Learn more about infections as a side effect of cancer treatment.

Other immediate side effects of AUTO transplants. The following side effects can develop right after the high doses of chemotherapy used for AUTO transplants:

Long-term side effects of AUTO transplants. Some transplant side effects happen months or years later. These can include:

An allogenic transplant is also called an ALLO transplant. In an ALLO transplant, the replacement cells come from another person, called a donor. After a round of chemotherapy and sometimes radiation therapy, you will receive the donor's healthy cells.

The side effects of an ALLO transplant are similar to common side effects of chemotherapy and radiation therapy. This includes a high risk for infections. You are also at risk of side effects caused by having another person's stem cells, including a risk of graft-versus-host disease (GVHD; see below). Many people also have a "graft-versus-cancer-cell effect" along with GVHD. This is because the new stem cells recognize and destroy cancer cells that are still in the body. It is the main way ALLO transplants work to cure cancers like leukemia.

Infection. After an ALLO transplant, your doctor will give you chemotherapy, with or without radiation therapy or other drugs, to keep your body's immune system from destroying the new donated cells. These treatments affect your immune system and make infection risk higher. A weak immune system makes you more likely to get infections.

You are at the highest risk of infection in the first few weeks after receiving the donor's cells. The risks lessen over time, but infection risk reduction is an important part of your long-term recovery.

Graft-versus-host disease (GVHD). Sometimes donor cells can attack your body, causing inflammation. This is a specific side effect of ALLO transplantation called GVHD. Even if your donor was a 100% match, you can still get GVHD. Your health care team can give you medication to prevent GVHD. If you still experience GVHD, your doctor will give you more medications to manage the condition. GVHD can be life-threatening in some cases.

There are 2 types of GVHD: acute and chronic. Both can range from mild to severe.

This form of GVHD happens in the first 3 months after an ALLO transplant. It often affects the skin, intestines, and liver. It can cause rashes, diarrhea, and jaundice. Jaundice is a liver problem that makes skin and the whites of the eyes look yellow.

The treatment for acute GVHD is to block T cells. T cells are white blood cells that help the immune system fight infections. Blocking them keeps your transplanted immune system from attacking your body's own cells.

Chronic GVHD usually develops more than 3 months after an ALLO transplant. It can last a few months or the rest of your life.

Chronic GVHD may or may not cause symptoms or need treatment. You may need treatment for specific problems. Some common problems of chronic GVHD include:

There are 2 medications approved by the U.S. Food and Drug Administration (FDA) to treat chronic graft-versus-host disease.

Ruxolitinib (Jakafi) in adults and children 12 years and older after 1 or more treatments with systemic therapy

Ibrutinib (Imbruvica) in children 1 year and older after 1 or more treatments with systemic therapy

Chronic GVHD can be treated with medications called corticosteroids. If this does not work well, you might take other medications to make your immune system less active.

Other immediate side effects. Side effects that can develop right after the high doses of chemotherapy used for ALLO transplantation include the following.

Late or long-term side effects. Some transplantation side effects can happen months or years later. These can include:

People who have less powerful chemotherapy treatments before their transplant tend to have fewer long-term physical effects.

Talk with your health care team about possible physical side effects of your bone marrow transplant, as well as what signs to watch for. They can help answer your questions and make a plan to manage short-term and long-term side effects.

Bone marrow transplantation is an extended medical process, and many people experience a variety of emotional and social challenges during this treatment and recovery. This can include anxiety and depression. It can also include the uncertainty and stress that cancer brings, self-image changes, changes in relationships with loved ones, feelings of isolation, and grieving losses from cancer and its treatment.

Be sure to share your feelings, including with your health care team. They want to know how you are feeling during and after transplantation. There are many ways to help support your mental health during this stressful time, including counseling, joining a support group, journaling, art therapy, mindfulness, and meditation.

It is important to talk often with your health care team about different types of side effects, before, during, and after your transplant. This helps you gather information and make decisions on treatment and care. Here are some possible questions to ask.

What tests will be done before the transplant process starts to check my general health?

When could I start to experience side effects during this process?

What specific side effects are common with this type of transplant? How can each one be managed or relieved?

Who should I call if I experience any side effects from my transplant?

What signs of an infection should I look out for?

What precautions to prevent infection should I follow? For how long?

What side effects should I tell my health care team right away?

If I will have an ALLO transplant, will I take any medications to prevent GVHD?

If I will have an ALLO transplant, what are the signs of GVHD that I should watch for?

What tests will I need later? How often?

What are the possible late effects of a transplant? How can they be managed or relieved?

How will having a transplant affect my daily life? Can I work? Can I exercise and do regular activities? Or, when can I restart these activities during my recovery?

Will having a transplant affect my sex life? If so, how and for how long?

Will having this transplant affect my ability to have a child in the future? If so, can you refer me to a fertility specialist before treatment begins?

Why is good nutrition important during and after a transplant? Should I meet with an oncology registered dietitian?

Who can I talk with about the emotional effects of cancer and this treatment?

What can I do at home to keep myself as healthy as possible?

What is a Bone Marrow Transplant (Stem Cell Transplant)?

Resources on Bone Marrow/Stem Cell Transplant

Coping With the Fear of Treatment-Related Side Effects

Survivorship

Bone Marrow Transplant and Older Adults

Be the Match: Life After Transplant

Be the Match: GVHD Signs and Symptoms

BMT InfoNet: Transplant Basics

National Bone Marrow Transplant Link: Publications on Side Effects and Survivorship

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Side Effects of a Bone Marrow Transplant (Stem Cell Transplant)

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RUDN Physician And Russian Scientists Investigate Long-term Effects Of Treating Diabetic Ulcers With Stem Cells  India Education Diary

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An organoid model of colorectal circulating tumor cells with stem cell ...

Cardiac Stem Cells Comments Off on An organoid model of colorectal circulating tumor cells with stem cell … | December 25th, 2022

A heart surgeon, Professor Massimo Caputo from the Bristol Heart Institute has stated he "saved the life" of a baby by carrying out a "world-first" operation using stem cells from placentas.

Professor Massimo Caputo used pioneering stem cell injections to correct baby Finley's heart defect and says he now hopes to develop the technology so children born with congenital cardiac disease won't need much surgical operations.

Finley was born with the main arteries in his heart positioned the wrong way round and at just four days old had his first open-heart surgery at Bristol Royal Hospital for Children

Unfortunately the surgery did not solve the issue and his heart function deteriorated significantly, with the left side of the heart suffering from a severe lack of blood flow.

His mother, Melissa, from Corsham, in Wiltshire, said: "We were prepared from the start that the odds of him surviving were not good.

"After 12 hours, Finley finally came out of surgery but he needed a heart and lung bypass machine to keep alive, and his heart function had deteriorated significantly."

After weeks in intensive care it looked like there was no way to treat Finley's condition and he was reliant on drugs to keep his heart going.

But a new procedure was tried, involving stem cells from a placenta bank.

Prof Caputo injected the cells directly into Finley's heart in the hope they would help damaged blood vessels grow.

The so-called "allogeneic" cells were grown by scientists at the Royal Free Hospital in London, and millions of them were injected into Finley's heart muscle.

Allogeneic cells have the ability to grow into tissue that is not rejected and in Finley's case, have regenerated damaged heart muscle.

"We weaned him from all the drugs he was on, we weaned him from ventilation," said Prof Caputo.

"He was discharged from ITU and is now a happy growing little boy."

Finley is now aged two years.

Using a bio-printer, a stem cell scaffold is made to repair abnormalities to valves in blood vessels, and to mend holes between the two main pumping chambers of the heart.

In cardiac surgery, artificial tissue is normally used on babies for cardiac repairs, but it can fail and it does not grow with the heart, so as the children grow, they require more operations.

A child might therefore have to go through the same heart operation multiple times throughout its childhood but Prof Caputo and his team say the stem cell technology could save the UK government an estimated 30,000 for every operation no longer needed.

Dr Stephen Minger, an expert in stem cell biology and director of SLM Blue Skies Innovations Ltd said;

"Most studies that I am aware of in adults with heart dysfunction or failure show only minimal therapeutic benefit with stem cell infusion.

"I'm happy that the clinical team will go on to do a standard clinical trial which should tell us if this was a 'one-off' success and also give us some better understanding of mechanisms behind this."

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Diagnosis

In the emergency room, a doctor may be able to rule out a spinal cord injury by examination, testing for sensory function and movement, and by asking some questions about the accident.

But if the injured person complains of neck pain, isn't fully awake, or has obvious signs of weakness or neurological injury, emergency diagnostic tests may be needed.

These tests can include:

A few days after injury, when some of the swelling might have subsided, your doctor will conduct a more comprehensive neurological exam to determine the level and completeness of your injury. This involves testing your muscle strength and your ability to sense light touch and pinprick sensations.

Unfortunately, there's no way to reverse damage to the spinal cord. But researchers are continually working on new treatments, including prostheses and medications, that might promote nerve cell regeneration or improve the function of the nerves that remain after a spinal cord injury.

In the meantime, spinal cord injury treatment focuses on preventing further injury and empowering people with a spinal cord injury to return to an active and productive life.

Urgent medical attention is critical to minimize the effects of head or neck trauma. Therefore, treatment for a spinal cord injury often begins at the accident scene.

Emergency personnel typically immobilize the spine as gently and quickly as possible using a rigid neck collar and a rigid carrying board, which they use during transport to the hospital.

In the emergency room, doctors focus on:

If you have a spinal cord injury, you'll usually be admitted to the intensive care unit for treatment. You might be transferred to a regional spine injury center that has a team of neurosurgeons, orthopedic surgeons, spinal cord medicine specialists, psychologists, nurses, therapists and social workers with expertise in spinal cord injury.

Medications. Methylprednisolone (Solu-Medrol) given through a vein in the arm (IV) has been used as a treatment option for an acute spinal cord injury in the past. But recent research has shown that the potential side effects, such as blood clots and pneumonia, from using this medication outweigh the benefits.

Because of this, methylprednisolone is no longer recommended for routine use after a spinal cord injury.

After the initial injury or condition stabilizes, doctors turn their attention to preventing secondary problems that may arise, such as deconditioning, muscle contractures, pressure ulcers, bowel and bladder issues, respiratory infections, and blood clots.

The length of your hospital stay will depend on your condition and the medical issues you face. Once you're well enough to participate in therapies and treatment, you might transfer to a rehabilitation facility.

Rehabilitation team members will begin to work with you while you're in the early stages of recovery. Your team might include a physical therapist, an occupational therapist, a rehabilitation nurse, a rehabilitation psychologist, a social worker, a dietitian, a recreation therapist, and a doctor who specializes in physical medicine (physiatrist) or spinal cord injuries.

During the initial stages of rehabilitation, therapists usually emphasize maintaining and strengthening muscle function, redeveloping fine motor skills, and learning ways to adapt to do day-to-day tasks.

You'll be educated on the effects of a spinal cord injury and how to prevent complications, and you'll be given advice on rebuilding your life and increasing your quality of life and independence.

You'll be taught many new skills, and you'll use equipment and technologies that can help you live on your own as much as possible. You'll be encouraged to resume your favorite hobbies, participate in social and fitness activities, and return to school or the workplace.

Medications might be used to manage some of the effects of spinal cord injury. These include medications to control pain and muscle spasticity, as well as medications that can improve bladder control, bowel control and sexual functioning.

Inventive medical devices can help people with a spinal cord injury become more independent and more mobile. These include:

Your doctor might not be able to give you a prognosis right away. Recovery, if it occurs, usually relates to the severity and level of the injury. The fastest rate of recovery is often seen in the first six months, but some people make small improvements for up to 1 to 2 years.

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

An accident that results in paralysis is a life-changing event. Suddenly having a disability can be frightening and confusing, and adapting is no easy task. You'll likely wonder how your spinal cord injury will affect your everyday activities, job, relationships and long-term happiness.

Recovery takes time, but many people who are paralyzed progress to lead productive and fulfilling lives. It's essential to stay motivated and get the support you need.

If you're newly injured, you and your family will likely experience a period of mourning. The grieving process, which is a normal, healthy part of your recovery, is different for everyone.

It's natural and important to grieve the loss of the way you were. But it's also necessary to set new goals and find ways to go forward.

You'll probably have concerns about how your injury will affect your lifestyle, your financial situation and your relationships. Grieving and emotional stress are normal and common.

However, if your grief is affecting your care, causing you to isolate yourself or prompting you to abuse alcohol or other drugs, you might want to talk to a social worker, psychologist or psychiatrist. Or you might find it helpful to join a support group of people with spinal cord injuries.

Talking with others who understand what you're going through can be encouraging, and you might find good advice on adapting areas of your home or work space to better meet your needs. Ask your doctor or rehabilitation specialist if there are support groups in your area.

One of the best ways to regain control of your life is to educate yourself about your injury and your options for gaining more independence. A range of driving equipment and vehicle modifications is available today.

The same is true of home modification products. Ramps, wider doors, special sinks, grab bars and easy-to-turn doorknobs make it possible for you to live more autonomously.

The costs of a spinal cord injury can be overwhelming, but you might be eligible for economic assistance or support services from the state or federal government or from charitable organizations. Your rehabilitation team can help you identify resources in your area.

Some friends and family members might be unsure about how to act around you. Being educated about your spinal cord injury and willing to educate others can benefit all of you.

Explain the effects of your injury and what others can do to help. But don't hesitate to tell friends and loved ones when they're helping too much. Although it may be uncomfortable at first, talking about your injury can strengthen your relationships with family and friends.

Your spinal cord injury might affect your body's sexual responsiveness. However, you're a sexual being with sexual desires. A fulfilling emotional and physical relationship is possible but requires communication, experimentation and patience.

A professional counselor can help you and your partner communicate your needs and feelings. Your doctor can provide the medical information you need regarding sexual health. You can have a satisfying future complete with intimacy and sexual pleasure.

As you learn more about your injury and treatment options, you might be surprised by all you can do. Thanks to new technologies, treatments and devices, people with spinal cord injuries play basketball and participate in track meets. They paint and take photographs. They get married, have and raise children, and have rewarding jobs.

Advances in stem cell research and nerve cell regeneration give hope for greater recovery for people with spinal cord injuries. And new treatments are being investigated for people with long-standing spinal cord injuries.

No one knows when new treatments will be available, but you can remain hopeful about the future of spinal cord research while living your life to the fullest today.

Traumatic spinal cord injuries are emergencies, and people who are injured might not be able to participate in their care at first.

A number of specialists will be involved in stabilizing the condition, including a doctor who specializes in nervous system disorders (neurologist) and a surgeon who specializes in spinal cord injuries and other nervous system problems (neurosurgeon), among others.

A doctor who specializes in spinal cord injuries will lead your rehabilitation team, which will include a variety of specialists.

If you have a possible spinal cord injury or you accompany someone who's had a spinal cord injury and can't provide the necessary information, here are some things you can do.

For a spinal cord injury, some basic questions to ask the doctor include:

Don't hesitate to ask other questions you have.

Your doctor is likely to ask questions, including:

Oct. 02, 2021

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28-year-old cancer patient at Nebraska Medicine advocates for diversity in bone marrow registry  KMTV 3 News Now Omaha

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28-year-old cancer patient at Nebraska Medicine advocates for diversity in bone marrow registry - KMTV 3 News Now Omaha

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1. Stem Cell Technologies and Applications Market Report 2022-2032  Yahoo Finance
2. Stem Cell Therapy Market is expected to generate a revenue of USD 296.14 Million by 2028, Globally, at 10.97% CAGR: Verified Market Research  PR Newswire
3. The Stem Cell Technologies and Applications market is projected to grow at a CAGR of 8.9% by 2032: Visiongain Reports Ltd  GlobeNewswire
4. Global Stem Cell Therapy Market Survey Insights,Outlook and Forecast 2023-2030 PRIZM News  PRIZM News
5. View Full Coverage on Google News

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Fred Hutch at ASH: Global insights on AML outcomes, COVID-19 and cancer, CD19 CAR T-cell therapy updates, latest on precision oncology and more  Newswise

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Burn wound healing involves a series of complex processes which are subject to intensive investigations to improve the outcomes, in particular, the healing time and the quality of the scar. Burn injuries, especially severe ones, are proving to have devastating effects on the affected patients. Stem cells have been recently applied in the field to promote superior healing of the wounds. Not only have stem cells been shown to promote better and faster healing of the burn wounds, but also they have decreased the inflammation levels with less scar progression and fibrosis. This review aims to highlight the beneficial therapeutic effect of stem cells in burn wound healing and to discuss the involved pathways and signaling molecules. The review covers various types of burn wound healing like skin and corneal burns, along with the alternative recent therapies being studied in the field of burn wound healing. The current reflection of the attitudes of people regarding the use of stem cells in burn wound healing is also stated.

The use of stem cell therapy is the yet to be discovered gold mine of science. A myriad of studies using stem cells are being done with promising results in various fields ranging from oncologic and hematologic diseases to organ transplants and wound healing. In the field of wound healing, the use of different types of stem cells has been reported for different types of wounds [13]. Burn wounds were of special interest due to the large number of cases of burns encountered nowadays, especially in the Middle Eastern Region and specifically in those areas with armed conflicts. Burn wounds have proven to be capable of having a devastating effect both functionally and cosmetically, necessitating the search for a better and more efficient cure. Being a very hot topic in the present field of research with constant studies and updates necessitated an updated review that encompasses the recent advances in stem cell therapy for burn wound healing in addition to relevant experimental studies. The literature was searched using the key words burn, stem cells, and wound healing. CINAHL, PubMed, EMBASE, and Medline were used as search engines to broaden the resources. The studies reported were not limited neither to humans nor by language and were mostly on animals unless otherwise specified. They are mostly reported in a chronological order of their publication dates, except when found relevant to group and mentioning some related studies consecutively.

Stem cells are undifferentiated pluripotential cells that are capable of producing other types of cells, including new stem cells identical to mother cells [4]. Stem cells can be of embryonal origin or adult origin, depending on the type of tissue they are derived from [4]. Embryonal stem cells are derived from either embryonal tissue or from germ cells in adults [4]. On the other hand, adult stem cells are derived from adult tissues of different organs, especially those with a high turnover rate such as intestines and bone marrow [4].

Stem cells have been implicated in the healing of wounds in general. However, the methods of application of the stem cells in burn wound healing are diverse, including topical application, local injection, intravenous or systemic injection, and dermal or carrier application. Several studies have shown the efficacy of stem cells in promoting faster and superior wound healing. Alexaki et al. [5] successfully used adipose derived mesenchymal stem cells in wound healing in mice and compared their effect with dermal fibroblasts. The application of stem cells in wounds promoted more efficient reepithelialization by their proliferative effect on keratinocytes [5]. Moreover, this effect of stem cells was found to be mediated by keratinocyte growth factor-1 (KGF-1) and platelet derived growth factor-BB (PDGF-BB) [5]. Amniotic fluid derived stem cells have also been used in wound healing. Skardal et al. [6] tested the effect of amniotic fluid derived stem cells in wound healing in a mouse model. Wound closure, reepithelialization, and angiogenesis were more rapid in mice treated with the stem cells in comparison to those treated with fibrin collagen gel only [6]. Additionally, stem cells did not integrate permanently in the tissue, thus, suggesting that their effect is due to released factors and not by direct interaction [6]. Additionally, bone marrow derived mesenchymal stem cells have also been used in wound healing. Leonardi et al. [7] utilized bone marrow derived stem cells in artificial dermal substitutes to promote wound healing. These stem cells were shown to increase vascular density in the wounds along with the rate of reepithelialization [7]. A study by Zhang et al. [8] examined the effect of activin signaling on the homing of stem cells to wound sites. It was also found that JNK and ERK signaling pathways were involved in activin signaling and eventually the homing of stem cells [8].

Concerning the physiology by which stem cells enhance the process of burn wound healing, several studies have been reported. Mansilla et al. [9] found evidence of cells in the bloodstream with identical phenotypes to mesenchymal bone marrow stem cells after acute large skin burns. Hence, it was concluded that these stem cells may have a role in promoting wound healing in burns. In a similar study, Fox et al. [10] reported increased levels of bone marrow derived endothelial progenitor cells in burn patients. These levels were proportional to the extent of the burn. The study also showed increased levels of angiogenic cytokines which may be involved in the signaling pathway for promoting the release of bone marrow derived stem cells. Focusing on the role of cytokines in burn wound healing, Payne et al. [11] studied the role of amnion derived cellular cytokine solution. In the study, Payne et al. used amnion derived multipotent progenitor cells to harvest cytokines and apply them in burn wound healing. Amnion derived cellular cytokine solution showed statistically significant improvement in the epithelialization of the burn wounds and the appearance of hair growth compared to controls [11]. In addition, the results demonstrated a faster epithelialization in burn wounds with increased frequency of application of the cytokines, further strengthening the role of stem cell derived cytokines in burn wound healing [11]. Furthermore, Foresta et al. [12] reported a positive linear correlation between endothelial progenitor cell blood levels and the total body surface area burnt. There was an increased level of endothelial progenitor cells in the bloodstream after escharectomy, posing a possible role of escharectomy in burn wound healing [12]. Additionally, stem cells could work by the release of bioactive peptides as proposed by Cabrera et al. [13] in their study where they showed that stem cells have an active role in burn wound healing by producing bioactive peptides, such as thymosin 4 and others.

More recent studies have also highlighted the role of stem cells in the process of wound healing in general and burn wound healing in specific. Koenen et al. [14] isolated acute wound fluids and chronic wound fluids and compared their effects on adipose tissue derived stem cell function in wounds. They came to the conclusion that acute wound fluids had a positive effect on the proliferation of adipose derived stem cells in wounds [14] while chronic wound fluids had a negative effect; the mentioned findings might explain the insufficient and slow healing process in chronic wounds due to a stem cell deficiency [14]. Furthermore, stem cells have been shown to decrease dermal fibrosis development in burn wound healing in mice [15]. Wu et al. performed a series of experiments which showed that bone marrow derived mesenchymal stem cells stimulate the formation of a basket weave organization of collagen in bleomycin treated skin, similar to normal skin [15]. Additionally, stem cell treatment of the skin decreased markers of myofibroblasts and downregulated type I collagen, leading to a decrease in the fibrosis that could have occurred to the skin [15]. Consequently, the role of stem cells in decreasing bleomycin induced fibrosis may be extrapolated to decrease fibrosis in burn wounds and improve their healing with less scar formation. Moreover, Lough et al. [16] performed a study in mice which showed a role for intestine derived human alpha defensin 5 in enhancing wound healing and decreasing its bacterial load. It induces leucine-rich repeat-containing G-protein-coupled receptors which are markers of adult epithelial stem cells both in skin and intestine [16]. Also implicated in the role of stem cells in burn wound healing is the role of SDF-1/CXCR4 signaling; Ding et al. [17] used interferon a2b in patients with burn wounds to suppress SDF-1/CXCR4 signaling. They found out that the decreased levels of signaling lead to better remodeling of hypertrophic scarring in the wounds [17]. Additional studies on the CXCR4 signaling pathway were done by Yang et al. [18] on irradiated mice. The mice having an overexpression of CXCR4, a receptor involved in the homing and migration of several stem cell types, showed an accelerated wound healing time [18]. Furthermore, Hu et al. [19] injected bone marrow derived mesenchymal stem cells into mice and studied the effect of blocking CXCR4 receptors. They found out that blocking the CXCL12/CXCR4 pathway, leading to activation of CXCR4, caused delayed wound closure in inflicted burn wounds. Moreover, CXCL12 levels were elevated in the burn wound one week after injury [19]. Hence, stem cells seem to be attracted to and attach to the burnt injury site by the CXCL12/CXCR4 pathway involving the CXCR4 receptors [18, 19]. The role of the ligand for the CXCR4 receptors, stromal cell derived factor-1 alpha (SDF-1a), has also been studied. L et al. [20] performed a study on the role of SDF-1a and its relation to the expression of miR-27b. It was found that SDF-1a expression was suppressed by direct binding of the miRNA to its 39UTR site [20]. As expected, miRNA expression was suppressed in wounds hence allowing better SDF-1a signaling and more homing of stem cells to the burn wounds [20]. In particular, miR-27b was found to be involved in the burn margins of wounds and in the mobilization of stem cells to the epidermis [20]. Chen et al. [21] performed experiments using porcine acellular dermal matrix on rats with inflicted 2nd degree burns. It stimulated collagen synthesis and stem cell proliferation and differentiation; porcine acellular matrix treated rats had a better and faster healing of the wounds.

Thus, in brief, the process of burn wound healing involves different types of growth factors, receptors, and cytokines. These factors are related to stem cell homing, differentiation, and proliferation. Additionally, when applied to burn wounds, they led to a better and faster healing process.

The use of stem cells for burn wound healing, as reported in the literature, dates back to 2003 with Shumakov et al. [22]. Shumakov et al. were the first to use mesenchymal bone marrow derived stem cells (BMSC) in burn wound healing and compared them to embryonic fibroblasts [22]. The experiments were done on rats where mesenchymal bone marrow derived stem cells were applied to wounds showing decreased cell infiltration of the wound and an accelerated formation of new vessels and granulation tissue in comparison with embryonic fibroblasts and controls (burn wounds with no transplanted cells) [22]. Hence, this study marked a new era in the research of burn wound healing by being the first to test the use of stem cells in this complex process. Following this, a study by Chunmeng et al. [23] found that systemic transplantation of dermis derived multipotent cells promoted the healing of wounds in irradiated rats compared to controls with no transplantation, noting that topical transplantation of the cells had no superior effect. In 2004, Rasulov et al. [24] were the first to report using bone marrow mesenchymal stem cells in humans; a female patient with extensive skin burns (IIIB 30% of body surface area) had the stem cells applied onto the burn surface. The application of stem cells caused faster wound healing and active neoangiogenesis [24]. Another study done by Rasulov et al. on rats also showed the superiority of stem cells in burn wound healing [25]. In the rat study, the application of mesenchymal stem cells on burns reduced cell infiltration, improved neoangeogenesis, and reduced the formation of granulation tissue [25]. The aforementioned conditions created a better medium for wound healing in burns. In a similar effort, Liu et al. [26] performed experiments on pigs where they applied collagen scaffolds with seeded mesenchymal stem cells onto the surface of inflicted burns; the latter were found to induce better burn wound healing with less contraction and better vascularization and keratinization. Moreover, in human cutaneous radiation wounds, Lataillade et al. [27, 28] reported two cases where stem cells where used to aid in burn wound healing. Mesenchymal stem cells were applied, in addition to surgical excision, flaps, and grafts, to burn wounds of cutaneous radiation patients. In these patients, the application of the mesenchymal stem cells decreased the levels of inflammation and promoted a better healing [27, 28]. Further on the role of stem cells in irradiated skin were the studies conducted by Dong et al. [29, 30], where they additionally inserted a vector of human beta defensin 2 into the stem cells. The mentioned studies showed a positive role for stem cells transfected with beta defensin 2 in burn wound healing by exhibiting antibacterial properties in infected burn wounds [29, 30]. In a similar experiment, Ha et al. [31] transfected mesenchymal stem cells with vectors of hepatocyte growth factor. The experiment, done on rats, compared the wound healing of a partial thickness burn treated with stem cells alone or stem cells transfected with hepatocyte growth factor [31]. The group treated with the transfected stem cells showed a significantly larger range of reepidermalization starting the first week, along with a thicker epidermis and lower content of collagen I at 3 weeks after burn [31]. In the same year (2010), Agay et al. [32] performed experimental studies by inflicting pigs with cutaneous radiation and studying the role of stem cells in the healing of the wounds. Intradermal mesenchymal stem cell injections were given locally in the affected area. They led to the accumulation of lymphocytes in the wound with better vascularization compared to controls (pigs with no injections of mesenchymal stem cells) [32]. Later on, Riccobono et al. [33] studied, in another experiment, the role of adipose tissue derived stem cells in the treatment of cutaneous radiation. Autologous, allogeneic, and acellular (empty, control) vehicles of adipose derived stem cells were grafted onto the burn wound areas [33]. Autologous but not allogeneic adipose derived stem cells were found to promote superior burn wound healing with no necrosis and decreased pain [33].

Aside to direct stem cell application to burn wounds, Kinoshita et al. [34] inflicted cutaneous radiation wounds to pigs and used expanders with and without basic fibroblast growth factor to determine their effect on burn wound healing. The group with basic fibroblast growth factor and expander showed greater proliferation of the dermis and epidermis along with increased neoangiogenesis [34]. Thus, basic fibroblast growth factor, which is known to promote the proliferation of mesenchymal stem cells, improved burn wound healing [34, 35].

In 2010, Yan et al. [36] studied the efficacy of porcine bone marrow derived mesenchymal stem cells combined with skin derived keratinocytes, both infected with recombinant retrovirus expressing human (h) platelet derived growth factor-A, in the healing of irradiated skin. The cells were loaded onto a cultured cutaneous substitute and compared their effect on healing with a cell-free cultured cutaneous substitute [36]. The substitute with cells stimulated faster healing, epithelialization, angiogenesis, and better granulation of the burn wound [36]. In another experiment, Collawn et al. [37] inflicted laser burn wounds to organotypic raft cultures. The burn wounds were treated with dermal grafts with and without adipose derived stromal cells [37]. The adipose derived stromal cell-containing grafts showed complete healing of the epidermis after two days, whereas the cell-free grafts still had areas of injury; hence, those stem cells had a role in promoting faster healing of the burnt areas [37]. More on cutaneous radiation treatment came from Xia et al. [38] who transfected human vascular endothelial growth factor 165 and human beta defensin 3 into bone marrow derived mesenchymal stem cells and used the cells to treat irradiated skin. The stem cell treated area, in comparison with cell-free controls, showed shorter healing times with better granulation and collagen deposition [38]. Additionally, Xue et al. [39] examined the effect of human mesenchymal stem cells in mouse models. Mice with inflicted burn wounds were injected locally, in the burn area, with the stem cells (controls injected cell-free injections) [39]. Wound healing was significantly faster when stem cells were included in the injection with an increased and denser neoangiogenesis [39]. Stem cell injections also had a role in resuming activity and regaining body weight more rapidly [39]. Similarly, Mansilla et al. [40] used mesenchymal stem cells in burn wound healing in pigs through an acellular dermal matrix embedded with anti-CD44 antibodies to promote homing and attachment of the stem cells [40]. This study concluded that the use of these dermal matrices with stem cells not only promoted better healing of the burn wound, but also stimulated the formation of hair follicles and regeneration of muscles and ribs [40].

Concerning stem cells from human umbilical cords, Liu et al. [41] studied the effect of human umbilical cord derived mesenchymal stem cells in the healing of severe burns inflicted in rats. The stem cells were intravenously injected into the affected rats [41]. Liu et al. found that the injection of the stem cells into the rats accelerated the wound healing compared to controls, decreased the count of inflammatory cells, downregulated interleukins 1 and 6, and increased the levels of interleukin 10 and TSG-6 [41]. Moreover, stem cell injected rats had increased neovascularization and VEGF levels [41]. Not only do stem cells promote faster wound healing in burns, but also they prevent the progression of burn injuries as showed by Singer et al. [42]. The latter performed an experiment while inflicting thermal burns to rats, with several rectangular burns on each rat separated by unburned interspaces [42]. Some of the rats received tail vein injections of mesenchymal stem cells, while others received saline injections [42]. After 7 days, all of the unburned spaces in the controls were necrotic [42]. However, 20% of the unburned spaces in rats with stem cells injections did not necrose [42]. Consequently, stem cells were also shown to play a possible role in the prevention of progression of burn injuries. Furthermore, in a study by Xu et al. [43], applying autologous bone marrow derived mesenchymal stem cells to grafted burn wounds, they demonstrated decreased contraction of the grafts.

In 2014, Yang et al. [44] attempted to integrate mesenchymal stem cells with fibrin glue into the dressing of burn wounds. They inflicted scald wounds on the back of rats and applied dressing with fibrin glue and stem cells in one group, fibrin glue only in the second, and no intervention in the third [44]. One month later, the treatment group with fibrin glue and stem cells showed significantly faster healing than the other two; moreover, this group had more proliferation of sebaceous glands and the appearance of hair follicle-like structures which were not present in the other groups [44]. In another experiment, Lough et al. [45] isolated leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6+) epithelial stem cells from the adnexal compartment of the skin of mice. They injected the harvested stem cells locally into inflicted burn wounds [45]. The wounds injected with stem cells showed a better healing along with increased vascular endothelial growth factor, platelet derived growth factor, and epidermal growth factor levels [45]. Stem cell injection also promoted the formation of nascent hair follicles and better neoangiogenesis in the wounds of the affected mice [45].

On the other hand, it is very pertinent to report another study in 2014 by Loder et al. [46] where they also tested the effect of adipose derived stem cells in the treatment of burns. The mice with inflicted burns that received stem cells injections showed no significant difference in comparison to controls (received saline injections) with respect to proliferation and vascularization [46]. Nevertheless, the role of stem cells in burn wound healing is a dynamic field and still under extensive research.

Another area of particular interest in the field of burn wound healing is the chemical burns of the cornea. In the year 2000, Dua and Azuara-Blanco [47] used autologous limbal stem cells for ocular surface reconstruction of the contralateral eye. It resulted in the formation of a better corneal surface with significant improvement in the vision and symptoms of the patients [47]. Several other experiments and trials using limbal stem cells showed similar results in inducing improvement of corneal healing and decreased neovascularization in both human (adults and children) and animal subjects [4853]. In 2007, Oh et al. [54] studied the therapeutic effects of mesenchymal stem cells on corneas with chemical burns. They reported that mesenchymal stem cell media and mesenchymal stem cell culture media (without the stem cells) reduced the inflammation and promoted neovascularization of the corneas [54]. They were also found to reduce the infiltration of CD4 cells, as well as IL-6, IL-10, and TGF-B1 levels. It is to be noted that the direct application of the stem cells provided superior results in the healing process in comparison with the stem cell culture media [54]. Another study by Ye et al. [55] utilized cyclophosphamide to suppress inflammatory reactions and the release of bone marrow stem cells into circulation. In this study, rabbits were inflicted with corneal alkali injuries. It was found that rabbits with an unsuppressed bone marrow had significantly greater reepithelialization of the corneas with clearer surfaces [55]. Thus, this study revealed the role of bone marrow cells in enhancing the healing of corneal chemical wounds. Furthermore, Sel et al. [56] inflicted alkali wounds on the corneal surfaces of mice and treated the corneas with bone marrow derived stem cells, CD117+ cells, or medium only as control. Reepithelialization of the wounds in the treatment groups was significantly faster than the control, with no difference in corneal transparency. Stem cells and CD117+ cells were absent from corneas after healing, thus suggesting that soluble factors may be responsible for the effect of the applied cells [56]. In a different study by Rama et al. [57], limbal stem cells were cultured on fibrin and used in corneal burns; not only did stem cells promote a better healing but also they had maintained a superior healing at a follow-up of 10 years later. Several other studies showed comparable results where mesenchymal derived or adipose derived stem cells promoted faster recovery of the corneal epithelium and decreased neovascularization, inflammation, and oxidative injury; moreover, stem cells stimulated the formation of clearer cornea media in some experiments [5861]. Additionally, Basu et al. [6264], in 2011 and 2012, reported a series of studies concerning the use of limbal stem cells in corneal burn wound healing. In the first study, Basu et al. [62] used limbal stem cells in corneal burn wound healing and followed them by penetrating keratoplasty procedures. Good results were observed but they were not compared to controls. However, in the second study, Basu et al. [63] observed that 66% of patients who failed primary procedures of corneal repair and who were subjected to a secondary limbal stem cell transplant on the affected cornea had successful improvement of the corneal surface with no neovascularization at a follow-up of two years. Later on, Sangwan et al. [64] used limbal biopsies from unaffected eyes and cultured them on amniotic membranes as substrates. Similar results to previous experiments were obtained with avascular epithelialization of the new corneal surfaces [64]. Furthermore and as demonstrated by Huang et al. [65], the use of allograft transplants of limbal stem cells in corneal burn wound healing also resulted in improved avascular corneal healing without the need for systemic immunosuppression. Pellegrini et al. [66] studied the biological factors that affected the stem cells role in corneal burn wound healing; the accurate number of stem cells used expressing high levels of the p63 transcription factor was shown to have important influence.

Stem cells do seem to have a very promising role in the treatment of burn wounds; however, other therapies are being developed to improve the treatment. For example, Klinger et al. [67] used fat injections in severe burn wounds as a trial to improve burn wound healing in humans. They did get results showing scar improvement and enhancement of tissue regeneration, but their study was limited to a small population [67]. In other studies, Auxenfans et al. [68] investigated the role of keratinocytes in improving wound healing in burns. They reported that keratinocytes induced a more rapid burn wound healing [68]. On the other hand, stromal vascular fraction has been also shown to play a possible role in enhancing burn wound healing [69]. Atalay et al. used isolated stromal vascular fraction in burn wound healing. It stimulated an increase in vascular endothelial growth factor and reduced the inflammation with an improved fibroblastic activity [69]. Additionally, Hussein et al. [70] studied the effect of Botox injections on burn wounds healing and found that Botox increased fibroblasts, TGF-B, and TNF-alpha levels and decreased inflammation, thus improving burn wound healing. Another recent study by Zhang et al. [71] showed a beneficial effect of heat shock protein 90 alpha on burn wound healing. It promoted faster healing and less inflammation. In addition, several other studies have examined the effects of different factors and substances such as curcumin, mast cell chymase, and phenytoin with hypericin on burn wound healing with promising results and better wound healing [7274].

Stem cells are commonly derived either from bone marrow, umbilical cord, adipose tissue, or skin. Natesan et al. [75] have even used debrided skin from severe burns as a source of stem cells for wound healing and regeneration. Hence, the adipose tissue that is discarded from burn wound debridement may now be of use for better wound healing. In addition, Natesan et al. [76], in another study, used isolated stem cells from debrided skin with fibrin and collagen based scaffolds. The dermal equivalents, created in the study, decreased wound contraction leading to a better matrix deposition and epithelialization [76]. Along the same line, van der Veen et al. [77] isolated mesenchymal stem cells from excised burn wound eschar. These stem cells showed similar abilities to adipose derived stem cells in differentiating into osteocytes, chondroblasts, and adipocytes [77].

A relatively recent approach by Li et al. [78] studied the role of electric fields in the migration of stem cells. They proved that epithelial stem cells migrate to the cathode in an induced electric field, knowing that endogenous electric fields exist naturally in wounds [78]. The migration of the stem cells was found to be proportional to the strength of the electric field and its duration, with the involvement of epidermal growth factor receptor and mitogen activated protein kinase-PI3K [78]. Hence, in addition to the use of stem cells in burn wounds, electric fields can be applied to the wounds to better direct their migration [78].

The role of stem cells in wound healing has been shown to be performed through several pathways, such as JNK and ERK59, and with the involvement of different factors and mediators, such as KGF-1 and PDGF-BB [5, 8]. Additionally, this role could also be carried out by the released factors and not only by direct integration of the stem cells into the wound scaffold or matrix [6].

Stem cells in burn wound healing have been found to follow the same mechanisms. The increased levels of stem cells in burn wounds suggested a possible enhancing role in aiding in the healing process [9, 10, 12, 13]. However, a lack of consistency of the outcome was documented. Different experiments may have used different amounts of purified stem cells, or stem cells at different stages of replication or differentiation in vitro, leading to what may seem different results. In brief, this review depicted the improved healing with stem cells qualitatively rather than quantitatively. To really demonstrate the value of different stem cells in the process of burn wound healing, more studies need to be done under optimal and well controlled conditions, aiming to measure a quantifiable improvement. Additionally, the excess use of stem cells may lead to unwanted results, such as increased fibrosis and thicker healed epithelium. Whether the effect is observed as a result of direct stem cell proliferation, or other induced substances and cells, needs to be studied in the future. Moreover, the role of cytokines released by stem cells along with bioactive peptides such as thymosin 4 has been documented to mediate the beneficial effect of the stem cell application in burn wound healing. Further data refer the superior healing probably not to the direct integration of the stem cells into the wound [11, 13]. Acute wound fluids were also shown to have a role in promoting faster healing of burn wounds, similarly reinforcing the role of mediators released by stem cells. Additionally, human alpha defensin 5 and the CXCL12/CXCR4 pathway with its signal SDF-1a were found to be inducers of stem cells in burn wounds [16, 18, 20].

In addition, stem cells have been shown to decrease cell infiltration, wound contraction, fibrosis, scar progression, and inflammation of burn wounds. Moreover, they have been found to promote faster burn wound healing and angiogenesis along with better granulation and the formation of hair follicles and sebaceous glands [15, 2245]. The studies reviewed showed positive results in both animal experiments and human trials, both in partial and full thickness injury burns. In addition, different ways of stem cell application have been used ranging from using stem cell scaffolds to systemic and intradermal injection [23, 25, 32]. Furthermore, the sources of stem cells used are multiple. They are derived from bone marrow, dermis, adipose tissue, and umbilical cords, among others [22, 23, 33, 41]. Stem cells have proved to be efficient not only in skin burns but also in corneal chemical burns, thus increasing the multiplicity of their use [5461].

Patients with burn wounds, especially those severely injured, tend to have lower quality of life [79]. The injury they suffer is not only physical but also psychological, affecting their jobs and relations with other people, especially their families [80, 81]. With the advance of burn wound treatment with time, patients self-esteem and quality of life have been improving [82, 83]. The hope is that the use of stem cells will open up a new arena of possibilities to improve the wound healing in burn patients, allowing patients to have faster healing, better scars, and a higher quality of life.

Stem cells have attracted many controversial public opinions over time. Many people argue that embryonic stem cell harvesting would be done by killing embryos which would be unethical [84]. Others would argue that even if embryos are used for stem cell research, it is not wrong. However, the path that this may lead to would be wrong such as embryo production for research purposes [84]. The public view towards the therapeutic use of stem cells has become more tolerant over time [85]. The role of educating people about the colossal potential for the use of stem cell has thus proven beneficial. People are now more educated about the different sources of stem cells and have become supportive of their use [85]. Regarding the acceptance of stem cells as an efficient therapy for burn wound healing in specific, a study done by Clover et al. [86] showed a very positive opinion. The biggest majority of people were willing to accept autologous stem cells, though a big percentage was also welcoming the idea of using allogeneic stem cells. These percentages did not differ between the use of stem cells for burn wounds or for the treatment of other diseases such as diabetes or Parkinsons [86].

In brief, the use of stem cells in burn wound healing appears to be very promising. While most studies were performed on animals, the application to humans is yet at its start. Hence, what is needed is more studies. Additionally, the signaling pathways followed by stem cells involved in the burn wound healing along with their factors and signals constitute a very dynamic and promising research field.

The authors declare that there is no conflict of interests regarding the publication of this paper.

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Adult stem cells maintain and repair tissues throughout the body

Embryonic stem cells are pluripotent cells derived from a 3 5 day old human embryo. They have the unique potential to develop into any of the other 200+ human cell types, and can significantly further our understanding of human development and diseases.

Embryonic stem cells also have important applications in drug development, and may one day be used to treat currently incurable conditions.

Stem cells are cells that have the potential to differentiate and give rise to other types of body cells. They are the basic materials from which all of the bodys specialized cells are made during whole-body development and, in adulthood, are used to maintain and repair body tissues. There are two types of human stem cells, and these are embryonic stem cells and adult stem cells.

Embryonic stem cells (ESCs) are stem cells derived from a 3 5 day old human embryo (AKA a blastocyst). ESCs are pluripotent, meaning they have the potential to become any of the other 200+ types of cells found in the human body. As the embryo develops, ESCs divide and differentiate to form the full complement of human body cells required for healthy function.

The first differentiation event in human embryos begins around 5 days after fertilization, so ESCs must be harvested before this time if they are to be used in medicine and research. At this early developmental stage, the cells of the embryo form an undifferentiated mass and have not yet taken on the characteristics or functions of specialized adult cells.

The ability of ESCs to develop into all other types of human cells makes them an invaluable research tool. Studies involving ESCs can advance our understanding of human development, disease treatment, and drug efficacy.

ESCs can be grown (or cultured) in a laboratory. When kept under the right conditions, stem cells will grow and divide indefinitely, without becoming differentiated. However, they will still maintain their ability to differentiate, making the ESC culture a convenient and renewable reservoir of human cells. When used in research, ECSs are converted into their desired cell types by manipulating the culture conditions.

Scientists can use stem cells to further their understanding of human development and diseases. By studying embryonic stem cells, researchers hope to learn how they differentiate to form tissues and organs, how diseases and conditions develop in these tissues, and how age affects their function.

Scientists can also use ESCs to test and develop new drugs and to help them identify new potential treatments for diseases like Parkinsons disease, heart failure, and spinal cord injuries.

ESCs have enormous potential in the development of restorative or regenerative medicine, in which damaged tissues are replaced by healthy ones. Currently, several stem cell therapies are possible and could be used to treat a variety of injuries and diseases. These include spinal cord injuries, retinal and macular degeneration, heart failure, type 1 diabetes, and tendon rupture.

However, research into the use of ESCs for regenerative medicine are ongoing, and better understanding is required before modern medicine can harness their full potential. In the future, scientists hope that stem cell therapies can be used to treat currently incurable or difficult to treat conditions, such as AIDS or certain types of cancer.

Currently, the most common stem cell therapy is multipotent hematopoietic stem cell (HSC) transplantation. This treatment involves the transplantation of hematopoietic (or blood) stem cells and is usually used to treat diseases affecting the blood cells, such as leukemia and anemia.

ESCs can also be used in the development of new drugs, which must be tested on living tissues to determine their efficacy and any possible side effects.

Stem cells cultured in the laboratory can be stimulated to differentiate into any type of human tissue, so they are commonly used in preclinical drug trials. Once the potential and risks of the new drug have been determined using stem cells, the treatment can be used in animal tests and, eventually, human clinical trials.

The discovery of ESCs has led to numerous breakthroughs in the field of medical research, and their potential as the basis for new therapies and drugs is enormous. However, there is ethical controversy surrounding the use of ESCs in research, primarily because harvesting these cells involves destroying a human embryo.

For those who believe that life begins at conception, this raises moral objections. Opponents of stem cell research believe that embryos have the same rights as any other human beings, and shouldnt be disposed of in the name of science.

Those who support the use of ESCs in medical research may argue that the embryos do not yet qualify as humans, as they are destroyed in the very early stages of development. ESCs are harvested at around day 5 of development when the embryo (or blastocyst) is nothing more than a mass of undifferentiated cells.

Embryos used as a source of ESCs are frequently obtained from IVF clinics, where they have been frozen following fertilization. Guidelines created by the National Institute of Health state that embryos can only be used for this purpose when they are no longer needed (meaning they will never be implanted in a womans uterus). Such embryos would eventually be discarded anyway, so it can be argued that they would be better used to advance medical research.

Adult stem cells (AKA somatic stem cells) are stem cells that are found in most adult tissues.

They can develop into other types of cells but, unlike, ESCs, they are not pluripotent (able to develop into any other type of cell). Adult stem cells are either multipotent (able to develop into a limited number of closely related cells) or unipotent (able to develop into just one type of cell).

Their main function is to maintain and repair the tissue in which they are found and to replace cells that die as a result of injury or disease.

Mesenchymal stem cells are found in many adult tissues, including the umbilical cord, bone marrow, and fat tissue. In the bone marrow, mesenchymal stem cells differentiate to form bone, cartilage, and fat cells.

Neural stem cells are found in the brain and develop into nerve cells and their supporting cells (glial cells).

Hematopoietic stem cells are found in the bone marrow and peripheral blood. They give rise to all kinds of blood cells, including red blood cells, white blood cells, and platelets.

Skin stem cells are found in the basal layer of the epidermis and form keratinocytes for the continuous regeneration of the epidermal layers.

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Embryonic Stem Cells - The Definitive Guide | Biology Dictionary

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From pro soccer hopeful to hip hop artist with illness and addiction along the way, Tymaz Bagbani releases debut album  Toronto Star

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From pro soccer hopeful to hip hop artist with illness and addiction along the way, Tymaz Bagbani releases debut album - Toronto Star

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Stem cell transplants are used to give back stem cells when the bone marrow has been destroyed by disease, chemotherapy (chemo), or radiation. Depending on where the stem cells come from, the transplant procedure may be called:

They can all be called hematopoietic stem cell transplants.

In a typical stem cell transplant for cancer, very high doses of chemo are used, sometimes along with radiation therapy, to try to kill all the cancer cells. This treatment also kills the stem cells in the bone marrow. This is called myeloablation or myeloablative therapy. Soon after treatment, stem cells are given (transplanted) to replace those that were destroyed. The replacement stem cells are given into a vein, much like ablood transfusion. The goal is that over time, the transplanted cells settle in the bone marrow, begin to grow and make healthy blood cells. This process is called engraftment.

There are 2 main types of transplants. They are named based on who donates the stem cells.

In this type of transplant, the first step is to remove or harvest your own stem cells. Your stem cells are removed from either your bone marrow or your blood, and then frozen. (You can learn more about this process at Whats It Like to Donate Stem Cells?) After you get high doses of chemo and/or radiation as your myeloablative therapy, the stem cells are thawed and given back to you.

Benefits of autologous stem cell transplant: One advantage of autologous stem cell transplant is that youre getting your own cells back. When you get your own stem cells back, you dont have to worry about them (called the engrafted cells or the graft) being rejected by your body.

Risks of autologous stem cell transplant: The grafts can still fail, which means the transplanted stem cells dont go into the bone marrow and make blood cells like they should. Also, autologous transplants cant produce the graft-versus-cancer effect. A possible disadvantage of an autologous transplant is that cancer cells might be collected along with the stem cells and then later put back into your body. Another disadvantage is that your immune system is the same as it was before your transplant. This means the cancer cells were able to escape attack from your immune system before, and may be able to do so again.

This kind of transplant is mainly used to treat certain leukemias, lymphomas, and multiple myeloma. Its sometimes used for other cancers, like testicular cancer and neuroblastoma, and certain cancers in children. Doctors can use autologous transplants for other diseases, too, like systemic sclerosis, multiple sclerosis (MS), and systemic lupus erythematosis (lupus).

To help prevent any remaining cancer cells from being transplanted along with stem cells, some centers treat the stem cells before theyre given back to the patient. This may be called purging. While this might work for some patients, there haven't been enough studies yet to know if this is really a benefit. A possible downside of purging is that some normal stem cells can be lost during this process. This may cause your body to take longer to start making normal blood cells, and you might have very low and unsafe levels of white blood cells or platelets for a longer time. This could increase the risk of infections or bleeding problems.

Another treatment to help kill cancer cells that might be in the returned stem cells involves giving anti-cancer drugs after the transplant. The stem cells are not treated. After transplant, the patient gets anti-cancer drugs to get rid of any cancer cells that may be in the body. This is called in vivo purging. For instance, lenalidomide (Revlimid) may be used in this way for multiple myeloma. The need to remove cancer cells from transplanted stem cells or transplant patients and the best way to do it continues to be researched.

Doing 2 autologous transplants in a row is known as a tandem transplant or a double autologous transplant. In this type of transplant, the patient gets 2 courses of high-dose chemo as myeloablative therapy, each followed by a transplant of their own stem cells. All of the stem cells needed are collected before the first high-dose chemo treatment, and half of them are used for each transplant. Usually, the 2 courses of chemo are given within 6 months. The second one is given after the patient recovers from the first one.

Tandem transplants have become the standard of care for certain cancers. High-risk types of the childhood cancer neuroblastoma and adult multiple myeloma are cancers where tandem transplants seem to show good results. But doctors dont always agree that these are really better than a single transplant for certain cancers. Because this treatment involves 2 transplants, the risk of serious outcomes is higher than for a single transplant.

Sometimes an autologous transplant followed by an allogeneic transplant might also be called a tandem transplant. (See Mini-transplants below.)

Allogeneic stem cell transplants use donor stem cells. In the most common type of allogeneic transplant, the stem cells come from a donor whose tissue type closely matches yours. (This is discussed in Matching patients and donors.) The best donor is a close family member, usually a brother or sister. If you dont have a good match in your family, a donor might be found in the general public through a national registry. This is sometimes called a MUD (matched unrelated donor) transplant. Transplants with a MUD are usually riskier than those with a relative who is a good match.

An allogeneic transplant works about the same way as an autologous transplant. Stem cells are collected from the donor and stored or frozen. After you get high doses of chemo and/or radiation as your myeloablative therapy, the donor's stem cells are thawed and given to you.

Blood taken from the placenta and umbilical cord of newborns is a type of allogeneic transplant. This small volume of cord blood has a high number of stem cells that tend to multiply quickly. Cord blood transplants are done for both adults and children. By 2017, an estimated 700,000 units (batches) of cord blood had been donated for public use. And, even more have been collected for private use. In some studies, the risk of a cancer not going away or coming back after a cord blood transplant was less than after an unrelated donor transplant.

Benefits of allogeneic stem cell transplant: The donor stem cells make their own immune cells, which could help kill any cancer cells that remain after high-dose treatment. This is called the graft-versus-cancer or graft-versus-tumor effect. Other advantages are that the donor can often be asked to donate more stem cells or even white blood cells if needed, and stem cells from healthy donors are free of cancer cells.

Risks of allogeneic stem cell transplants: The transplant, or graft, might not take that is, the transplanted donor stem cells could die or be destroyed by the patients body before settling in the bone marrow. Another risk is that the immune cells from the donor may not just attack the cancer cells they could attack healthy cells in the patients body. This is called graft-versus-host disease. There is also a very small risk of certain infections from the donor cells, even though donors are tested before they donate. A higher risk comes from infections you had previously, and which your immune system has had under control. These infections may surface after allogeneic transplant because your immune system is held in check (suppressed) by medicines called immunosuppressive drugs. Such infections can cause serious problems and even death.

Allogeneic transplant is most often used to treat certain types of leukemia, lymphomas, multiple myeloma, myelodysplastic syndrome, and other bone marrow disorders such as aplastic anemia.

For some people, age or certain health conditions make it more risky to do myeloablative therapy that wipes out all of their bone marrow before a transplant. For those people, doctors can use a type of allogeneic transplant thats sometimes called a mini-transplant. Your doctor might refer to it as a non-myeloablative transplant or mention reduced-intensity conditioning (RIC). Patients getting a mini transplant typically get lower doses of chemo and/or radiation than if they were getting a standard myeloablative transplant. The goal in the mini-transplant is to kill some of the cancer cells (which will also kill some of the bone marrow), and suppress the immune system just enough to allow donor stem cells to settle in the bone marrow.

Unlike the standard allogeneic transplant, cells from both the donor and the patient exist together in the patients body for some time after a mini-transplant. But slowly, over the course of months, the donor cells take over the bone marrow and replace the patients own bone marrow cells. These new cells can then develop an immune response to the cancer and help kill off the patients cancer cells the graft-versus-cancer effect.

One advantage of a mini-transplant is that it uses lower doses of chemo and/or radiation. And because the stem cells arent all killed, blood cell counts dont drop as low while waiting for the new stem cells to start making normal blood cells. This makes it especially useful for older patients and those with other health problems. Rarely, it may be used in patients who have already had a transplant.

Mini-transplants treat some diseases better than others. They may not work well for patients with a lot of cancer in their body or people with fast-growing cancers. Also, although there might be fewer side effects from chemo and radiation than those from a standard allogeneic transplant, the risk of graft-versus-host disease is the same. Some studies have shown that for some cancers and some other blood conditions, both adults and children can have the same kinds of results with a mini-transplant as compared to a standard transplant.

This is a special kind of allogeneic transplant that can only be used when the patient has an identical sibling (twin or triplet) someone who has the exact same tissue type. An advantage of syngeneic stem cell transplant is that graft-versus-host disease will not be a problem. Also, there are no cancer cells in the transplanted stem cells, as there might be in an autologous transplant.

A disadvantage is that because the new immune system is so much like the recipients immune system, theres no graft-versus-cancer effect. Every effort must be made to destroy all the cancer cells before the transplant is done to help keep the cancer from coming back.

Improvements have been made in the use of family members as donors. This kind of transplant is called ahalf-match (haploidentical) transplant for people who dont have fully matching or identical family member. This can be another option to consider, along with cord blood transplant and matched unrelated donor (MUD) transplant.

If possible, it is very important that the donor and recipient are a close tissue match to avoid graft rejection. Graft rejection happens when the recipients immune system recognizes the donor cells as foreign and tries to destroy them as it would a bacteria or virus. Graft rejection can lead to graft failure, but its rare when the donor and recipient are well matched.

A more common problem is that when the donor stem cells make their own immune cells, the new cells may see the patients cells as foreign and attack their new home. This is called graft-versus-host disease. (See Stem Cell Transplant Side Effects for more on this). The new, grafted stem cells attack the body of the person who got the transplant. This is another reason its so important to find the closest match possible.

Many factors play a role in how the immune system knows the difference between self and non-self, but the most important for transplants is the human leukocyte antigen (HLA) system. Human leukocyte antigens are proteins found on the surface of most cells. They make up a persons tissue type, which is different from a persons blood type.

Each person has a number of pairs of HLA antigens. We inherit them from both of our parents and, in turn, pass them on to our children. Doctors try to match these antigens when finding a donor for a person getting a stem cell transplant.

How well the donors and recipients HLA tissue types match plays a large part in whether the transplant will work. A match is best when all 6 of the known major HLA antigens are the same a 6 out of 6 match. People with these matches have a lower chance of graft-versus-host disease, graft rejection, having a weak immune system, and getting serious infections. For bone marrow and peripheral blood stem cell transplants, sometimes a donor with a single mismatched antigen is used a 5 out of 6 match. For cord blood transplants a perfect HLA match doesnt seem to be as important, and even a sample with a couple of mismatched antigens may be OK.

Doctors keep learning more about better ways to match donors. Today, fewer tests may be needed for siblings, since their cells vary less than an unrelated donor. But to reduce the risks of mismatched types between unrelated donors, more than the basic 6 HLA antigens may be tested. For example, sometimes doctors to try and get a 10 out of 10 match. Certain transplant centers now require high-resolution matching, which looks more deeply into tissue types and allow more specific HLA matching.

There are thousands of different combinations of possible HLA tissue types. This can make it hard to find an exact match. HLA antigens are inherited from both parents. If possible, the search for a donor usually starts with the patients brothers and sisters (siblings), who have the same parents as the patient. The chance that any one sibling would be a perfect match (that is, that you both received the same set of HLA antigens from each of your parents) is 1 out of 4.

If a sibling is not a good match, the search could then move on to relatives who are less likely to be a good match parents, half siblings, and extended family, such as aunts, uncles, or cousins. (Spouses are no more likely to be good matches than other people who are not related.) If no relatives are found to be a close match, the transplant team will widen the search to the general public.

As unlikely as it seems, its possible to find a good match with a stranger. To help with this process, the team will use transplant registries, like those listed here. Registries serve as matchmakers between patients and volunteer donors. They can search for and access millions of possible donors and hundreds of thousands of cord blood units.

Be the Match (formerly the National Marrow Donor Program)Toll-free number: 1-800-MARROW-2 (1-800-627-7692)Website: http://www.bethematch.org

Blood & Marrow Transplant Information NetworkToll-free number: 1-888-597-7674Website: http://www.bmtinfonet.org

Depending on a persons tissue typing, several other international registries also are available. Sometimes the best matches are found in people with a similar racial or ethnic background. When compared to other ethnic groups, white people have a better chance of finding a perfect match for stem cell transplant among unrelated donors. This is because ethnic groups have differing HLA types, and in the past there was less diversity in donor registries, or fewer non-White donors. However, the chances of finding an unrelated donor match improve each year, as more volunteers become aware of registries and sign up for them.

Finding an unrelated donor can take months, though cord blood may be a little faster. A single match can require going through millions of records. Also, now that transplant centers are more often using high-resolution tests, matching is becoming more complex. Perfect 10 out of 10 matches at that level are much harder to find. But transplant teams are also getting better at figuring out what kinds of mismatches can be tolerated in which particular situations that is, which mismatched antigens are less likely to affect transplant success and survival.

Keep in mind that there are stages to this process there may be several matches that look promising but dont work out as hoped. The team and registry will keep looking for the best possible match for you. If your team finds an adult donor through a transplant registry, the registry will contact the donor to set up the final testing and donation. If your team finds matching cord blood, the registry will have the cord blood sent to your transplant center.

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Types of Stem Cell and Bone Marrow Transplants - American Cancer Society

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When the decision is made to have a stem cell or bone marrow transplant, there are several steps in theprocess. The steps are much the same, no matter what type of transplant youre going to have.

You will first be evaluated to find out if you are eligible for a transplant. A transplant is very hard on your body. For many people, transplants can mean a cure, but for some people, problems can lead to severe complications or even death. Youll want to weigh the benefits and risks before you start.

Transplants can also be hard emotionally. They often require being in the hospital, being isolated, and theres a high risk of side effects. Many of the effects are short-term, but some problems can go on for years. This can mean changes in the way you live your life. For some people its just for a while, but for others, the changes may be lifelong. Some of the side effects are really unpleasant and can be serious. Your cancer care team will do everything they can to make you comfortable, but some of the side effects may not be completely controlled or relieved.

Before you have a transplant, you need to discuss the transplant process and all its effects with your doctors. It also helps to talk with others who have already had transplants.

Its also very hard going through weeks and months of not knowing how your transplant will turn out. This takes a lot of time and emotional energy from the patient, caregivers, and loved ones. Its very important to have the support of those close to you. For example, youll need a responsible adult who will be with you to give you medicines, help watch for problems, and stay in touch with your transplant team after you go home. Your transplant team will help you and your caregiver learn what you need to know. The team can also help you and your loved ones work through the ups and downs as you prepare for and go through the transplant.

Many different medical tests will be done, and questions will be asked to try to find out how well you can handle the transplant process. These might include:

You will also talk about your health insurance coverage and related costs that you might have to pay.

You may have a central venous catheter (CVC) put into a large vein in your chest. This is most often done as outpatient surgery, and usually only local anesthesia is needed (the place where the catheter goes in is made numb). Nurses will use the catheter to draw blood and give you medicines.

If youre getting an autologous transplant, a special catheter can be placed that can also be used when your stem cells are being removed or harvested.

The CVC will stay in during your treatment and for some time afterward, usually until your transplanted stem cells have engrafted and your blood counts are on a steady climb to normal.

Younger people, people who are in the early stages of disease, or those who have not already had a lot of treatment, often do better with transplants. Some transplant centers set age limits. Some people also may not be eligible for transplant if they have other major health problems, such as serious heart, lung, liver, or kidney disease. A mini-transplant, described under Allogeneic stem cell transplant in Types of Stem Cell Transplants for Cancer Treatment may be an option for some of these people.

The hospitals transplant team will decide if you need to be in the hospital to have your transplant, if it will be done in an outpatient center, or if you will be in the hospital just for parts of it. If you have to be in the hospital, you will probably go in the day before pre-transplant chemo or radiation treatment begins (see the next section), the transplant team makes sure you and your family understand the process and want to go forward with it.

If you will be having all or part of your transplant as an outpatient, youll need to be very near the transplant center during the early stages. Youll need a family member or loved one to be a caregiver who can stay with you all the time. You and the caregiver will also need reliable transportation to and from the clinic. The transplant team will be watching you closely for complications, so expect to be at the clinic every day for a few weeks. You may still need to be in the hospital if your situation changes or if you start having complications.

To reduce the chance of infection during treatment, patients who are in the hospital are put in private rooms that have special air filters. The room may also have a protective barrier to separate it from other rooms and hallways. Some have an air pressure system that makes sure no unclean outside air gets into the room. If youre going to be treated as an outpatient, you will get instructions on avoiding infection. Usually, people who have transplants are in a separate, special part of the hospital to keep as many germs away as possible.

The transplant experience can be overwhelming. Your transplant team will be there to help you prepare for the process physically and emotionally and to discuss your needs. Every effort will be made to answer questions so you and your family fully understand what will be happening to you as you go through transplant.

Its important for you and your family to know what to expect, because once conditioning treatment begins (see the next section), theres no going back there can be serious problems if treatment is stopped at any time during transplant.

Having a transplant takes a serious commitment from you and your caregiver and family, so it is important to know exactly what to expect.

Conditioning, also known as pre-transplant treatment,bone marrow preparation, or myeloablation, is usually treatment with high-dose chemo and/or radiation therapy. Its the first step in the transplant process and typically takes a week or two. Its done for one or more of these reasons:

The conditioning treatment is different for every transplant. Your treatment will be planned based on the type of cancer you have, the type of transplant, and any chemo or radiation therapy youve had in the past.

If chemo is part of your treatment plan, it will be given in your central venous catheter and/or as pills. If radiation therapy is planned, its given to the entire body (called total body irradiation or TBI). TBI may be given in a single treatment session or in divided doses over a few days.

This phase of the transplant can be very uncomfortable because very high treatment doses are used. Chemo and radiation side effects can make you sick, and it may take you months to fully recover. A very common problem is mouth sores that will need to be treated with strong pain medicines. You may also have nausea, vomiting, be unable to eat, lose your hair, and have lung or breathing problems.

Conditioning can also cause premature menopause in women and often makes people sterile (unable to have children). (See Stem Cell Transplant Side Effects.)

After the conditioning treatment, youll be given a couple of days to rest before getting the stem cells. They will be given through your central venous catheter, much like a blood transfusion. If the stem cells were frozen, you might get some drugs before the stem cells are given. These drugs are used to help reduce your risk of reacting to the preservatives that are used when freezing the cells.

If the stem cells were frozen, they are thawed in warm water then given right away. There may be more than 1 bag of stem cells. For allogeneic or syngeneic transplants, the donor cells may be harvested (removed) in an operating room, and then processed in the lab right away. Once they are ready, the cells are brought in and given to you theyre not frozen. The length of time it takes to get all the stem cells depends on how much fluid the stem cells are in.

You will be awake for this process, and it doesnt hurt. This is a big step and often has great meaning for patientsand their families. Many people consider this their rebirth or chance at a second life. They may celebrate this day as they would their actual birthday.

Side effects from the infusion are rare and usually mild. The preserving agent used when freezing the stem cells causes many of the side effects. For instance, you might have a strong taste of garlic or creamed corn in your mouth. Sucking on candy or sipping flavored drinks during and after the infusion can help with the taste. Your body will also smell like this. The smell may bother those around you, but you might not even notice it. The smell, along with the taste, may last for a few days, but slowly fades away. Often having cut up oranges in the room will offset the odor. Patients who have transplants from cells that were not frozen do not have this problem because the cells are not mixed with the preserving agent.

Other side effects you might have during and right after the stem cell infusion include:

Again, side effects are rare and usually mild. If they do happen, they are treated as needed. The stem cell infusion must always be completed.

The recovery stage begins after the stem cell infusion. During this time, you and your family wait for the cells to engraft, or take, after which they start to multiply and make new blood cells. The time it takes to start seeing a steady return to normal blood counts varies depending on the patient and the transplant type, but its usually about 2 to 6 weeks. Youll be in the hospital or visit the transplant center daily for a number of weeks.

During the first couple of weeks youll have low numbers of red and white blood cells and platelets. Right after transplant, when your counts are the lowest, you may be given antibiotics to help keep you from getting infections. You may get a combination of anti-bacterial, anti-fungal, and anti-viral drugs. These are usually given until your white blood cell count reaches a certain level. Still, you can have problems, such as infection from too few white blood cells (neutropenia), or bleeding from too few platelets (thrombocytopenia). Many patients have high fevers and need IV antibiotics to treat serious infections. Transfusions of red blood cells and platelets are often needed until the bone marrow starts working and new blood cells are being made by the infused stem cells.

Except for graft-versus-host disease, which only happens with allogeneic transplants, the side effects from autologous, allogeneic, and syngeneic stem cell transplants are much the same. Problems may include stomach, heart, lung, liver, or kidney problems. (Stem Cell Transplant Side Effects goes into the details.) You might also go through feelings of distress, anxiety, depression, joy, or anger. Adjusting emotionally after the stem cells can be hard because of the length of time you feel ill and isolated from others.

You might feel as if you are on an emotional roller coaster during this time. Support and encouragement from family, friends, and the transplant team are very important to get you through the challenges after transplant.

The discharge process actually begins weeks before your transplant. It starts with the transplant team teaching you and your primary (main) caregiver about:

For the most part, transplant centers dont send patients home until they meet the following criteria:

(Why Are Stem Cell Transplants Used as Cancer Treatment? has more information about neutrophils, platelets, and hematocrit).

If you do not meet all of these requirements, but still dont need the intensive care of the transplant unit, you might be moved to another oncology unit. When you do go home, you might need to stay near the transplant center for some time, depending on your condition.

The process of stem cell transplant doesnt end when you go home. Youll feel tired, and some people have physical or mental health problems in the rehabilitation period. You might still be taking a lot of medicines. These ongoing needs must now be managed at home, so caregiver and friend/family support is very important.

Transplant patients are followed closely during rehab. You might need daily or weekly exams along with things like blood tests, and maybe other tests, too. During early rehab, you also might need blood and platelet transfusions, antibiotics, or other treatments. At first youll need to see your transplant team often, maybe even every day, but youll progress to less frequent visits if things are going well. It can take 6 to 12 months, or even longer, for blood counts to get close to normal and your immune system to work well. During this time, your team will still be closely watching you.

Some problems might show up as much as a year or more after the stem cells were infused. They can include:

Other problems can also come up, such as:

Your transplant team is still there to help you, even though the transplant happened months ago. Its important that you tell them about any problems you are having they can help you get the support you need to manage the changes that you are going through. They can also help you know if problems are serious, or a normal part of recovery. The National Bone Marrow Transplant Link helps patients, caregivers, and families by providing information and support services before, during, and after transplant. They can be reached at 1-800-LINK-BMT (1-800-546-5268) or online at http://www.nbmtlink.org.

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Getting a Stem Cell or Bone Marrow Transplant - American Cancer Society

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Woman, 41, With Bubbles In Her Urine Dismissed By Doctors. Turns Out To Have The Blood Cancer Multiple Myeloma.  SurvivorNet

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Woman, 41, With Bubbles In Her Urine Dismissed By Doctors. Turns Out To Have The Blood Cancer Multiple Myeloma. - SurvivorNet

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Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the potential to differentiate into various types of cells including skeletal muscle cells. The approach of converting ESCs/iPSCs into skeletal muscle cells offers hope for patients afflicted with the skeletal muscle diseases such as the Duchenne muscular dystrophy (DMD). Patient-derived iPSCs are an especially ideal cell source to obtain an unlimited number of myogenic cells that escape immune rejection after engraftment. Currently, there are several approaches to induce differentiation of ESCs and iPSCs to skeletal muscle. A key to the generation of skeletal muscle cells from ESCs/iPSCs is the mimicking of embryonic mesodermal induction followed by myogenic induction. Thus, current approaches of skeletal muscle cell induction of ESCs/iPSCs utilize techniques including overexpression of myogenic transcription factors such as MyoD or Pax3, using small molecules to induce mesodermal cells followed by myogenic progenitor cells, and utilizing epigenetic myogenic memory existing in muscle cell-derived iPSCs. This review summarizes the current methods used in myogenic differentiation and highlights areas of recent improvement.

Duchenne muscular dystrophy (DMD) is a genetic disease affecting approximately 1 in 3500 male live births [1]. It results in progressive degeneration of skeletal muscle causing complete paralysis, respiratory and cardiac complications, and ultimately death. Normal symptoms include the delay of motor milestones including the ability to sit and stand independently. DMD is caused by an absence of functional dystrophin protein and skeletal muscle stem cells, as well as the exhaustion of satellite cells following many rounds of muscle degeneration and regeneration [2]. The dystrophin gene is primarily responsible for connecting and maintaining the stability of the cytoskeleton of muscle fibers during contraction and relaxation. Despite the low frequency of occurrence, this disease is incurable and will cause debilitation of the muscle and eventual death in 20 to 30 year olds with recessive X-linked form of muscular dystrophy. Although there are no current treatments developed for DMD, there are several experimental therapies such as stem cell therapies.

Skeletal muscle is known to be a regenerative tissue in the body. This muscle regeneration is mediated by muscle satellite cells, a stem cell population for skeletal muscle [3, 4]. Although satellite cells exhibit some multipotential differentiation capabilities [5], their primary differentiation fate is skeletal muscle cells in normal muscle regeneration. Ex vivo expanded satellite cell-derived myoblasts can be integrated into muscle fibers following injection into damaged muscle, acting as a proof-of-concept of myoblast-mediated cell therapy for muscular dystrophies [69]. However, severe limitations exist in relation to human therapy. The number of available satellite cells or myoblasts from human biopsies is limited. In addition, the poor cell survival and low contribution of transplanted cells have hindered practical application in patients [6, 8, 9]. Human-induced pluripotent stem cells (hiPSCs) are adult cells that have been genetically reprogrammed to an embryonic stem cell- (ESC-) like state by being forced to express genes and factors important for maintaining the defining properties of ESCs. hiPSCs can be generated from a wide variety of somatic cells [10, 11]. They have the ability to self-renew and successfully turn into any type of cells. With their ability to capture genetic diversity of DMD in an accessible culture system, hiPSCs represent an attractive source for generating myogenic cells for drug screening.

The ESC/iPSC differentiation follows the steps of embryonic development. The origin of skeletal muscle precursor cells comes from the mesodermal lineage, which give rise to skeletal muscle, cardiac muscle, bone, and blood cells. Mesoderm subsequently undergoes unsegmented presomitic mesoderm followed by segmented compartments termed somites from anterior to caudal direction. Dermomyotome is an epithelial cell layer making up the dorsal part of the somite underneath the ectoderm. Dermomyotome expresses Pax3 and Pax7 and gives rise to dermis, skeletal muscle cells, endothelial cells, and vascular smooth muscle [12]. Dermomyotome also serves as a tissue for secreted signaling molecules to the neural tube, notochord, and sclerotome [13, 14]. Upon signals from the neural tube and notochord, the dorsomedial lip of dermomyotome initiates and expresses skeletal muscle-specific transcription factors such as MyoD and Myf5 to differentiate into myogenic cells termed myoblasts. Myoblasts then migrate beneath the dermomyotome to form myotome. Eventually, these myoblasts fuse with each other to form embryonic muscle fibers. ESCs/iPSCs mimic these steps toward differentiation of skeletal muscle cells. Many studies utilize methods of overexpression of muscle-related transcription factors such as MyoD or Pax3 [15], or the addition of small molecules which activate or inhibit myogenic signaling during development. Several studies show that iPSCs retain a bias to form their cell type of origin due to an epigenetic memory [1619], although other papers indicate that such epigenetic memory is erased during the reprogramming processes [2022]. Therefore, this phenomenon is not completely understood at the moment. In light of these developments, we have recently established mouse myoblast-derived iPSCs capable of unlimited expansion [23]. Our data demonstrates that these iPSCs show higher myogenic differentiation potential compared to fibroblast-derived iPSCs. Thus, myogenic precursor cells generated from human myoblast-derived iPSCs expanded ex vivo should provide an attractive cell source for DMD therapy. However, since DMD is a systemic muscle disease, systemic delivery of myoblasts needs to be established for efficient cell-based therapy.

During developmental myogenesis, presomitic mesoderm is first formed by Mesogenin1 upregulation, which is a master regulator of presomitic mesoderm [24]. Then, the paired box transcription factor Pax3 gene begins to be expressed from presomitic mesoderm to dermomyotome [25]. Following Pax3 expression, Pax7 is also expressed in the dermomyotome [26], and then Myf5 and MyoD, skeletal muscle-specific transcription factor genes, begin to be expressed in the dorsomedial lip of the dermomyotome in order to give rise to myoblasts which migrate beneath the dermomyotome to form the myotome. Subsequently, Mrf4 and Myogenin, other skeletal muscle-specific transcription factor genes, followed by skeletal muscle structural genes such as myosin heavy chain (MyHC), are expressed in the myotome for myogenic terminal differentiation (Figure 1) [27, 28]. Pax3 directly and indirectly regulates Myf5 expression in order to induce myotomal cells. Dorsal neural tube-derived Wnt proteins and floor plate cells in neural tube and notochord-derived sonic hedgehog (Shh) positively regulate myotome formation [13, 29]. Neural crest cells migrating from dorsal neural tubes are also involved in myotome formation: Migrating neural crest cells come across the dorsomedial lip of the dermomyotome, and neural crest cell-expressing Delta1 is transiently able to activate Notch1 in the dermomyotome, resulting in conversion of Pax3/7(+) myogenic progenitor cells into MyoD/Myf5(+) myotomal myoblasts [30, 31]. By contrast, bone morphogenetic proteins (BMPs) secreted from lateral plate mesoderm are a negative regulator for the myotome formation by maintaining Pax3/Pax7(+) myogenic progenitor cells [29, 32]. Pax3 also regulates cell migration of myogenic progenitor cells from ventrolateral lip of dermomyotome to the limb bud [33]. Pax3 mutant mice lack limb muscle but trunk muscle development is relatively normal [34]. Pax3/Pax7 double knockout mice display failed generation of myogenic cells, suggesting that Pax3 and Pax7 are critical for proper embryonic myogenesis [35]. Therefore, both Pax3 and Pax7 are also considered master transcription factors for the specification of myogenic progenitor cells. Importantly, MyoD was identified as the first master transcription factor for myogenic specification since MyoD is directly able to reprogram nonmuscle cell type to myogenic lineage when overexpressed [3638]. In addition, genetic ablation of MyoD family gene(s) via a homologous gene recombination technique causes severe myogenic developmental or regeneration defects [3945]. Finally, genetic ablation of combinatory MyoD family genes demonstrates that MyoD/:Myf5/:MRF4/ mice do not form any skeletal muscle during embryogenesis, indicating the essential roles in skeletal muscle development of MyoD family genes [28, 46]. It was proven that Pax3 also possesses myogenic specification capability since ectopic expression of Pax3 is sufficient to induce myogenic programs in both paraxial and lateral plate mesoderm as well as in the neural tube during chicken embryogenesis [47]. In addition, genetic ablation of Pax3 and Myf5 display complete defects of body skeletal muscle formation during mouse embryogenesis [48]. Finally, overexpression of Pax7 can convert CD45(+)Sca-1(+) hematopoietic cells into skeletal muscle cells [49]. From these notions, overexpression of myogenic master transcription factors such as MyoD or Pax3 has become the major strategy for myogenic induction in nonmuscle cells, including ES/iPSCs.

The overexpression of MyoD approach to induce myogenic cells from mESCs was first described by Dekel et al. in 1992. This has been a standard approach for the myogenic induction from pluripotent stem cells (Table 1). Ozasa et al. first utilized Tet-Off systems for MyoD overexpression in mESCs and showed desmin(+) and MyHC(+) myotubes in vitro [50]. Warren et al. transfected synthetic MyoD mRNA in to hiPSCs for 3 days, which resulted in myogenic differentiation (around 40%) with expression of myogenin and MyHC [51]. Tanaka et al. utilized a PiggyBac transposon system to overexpress MyoD in hiPSCs. The PiggyBac transposon system allows cDNAs to stably integrate into the genome for efficient gene expression. After integration, around 70 to 90% of myogenic cells were induced in hiPSC cultures within 5 days [52]. This study also utilized Miyoshi myopathy patient-derived hiPSCs for the MyoD-mediated myogenic differentiation. Miyoshi myopathy is a congenital distal myopathy caused by defective muscle membrane repair due to mutations in dysferlin gene. The patient-derived hiPSC-myogenic cells will be able to provide the opportunity for therapeutic drug screening. Abujarour et al. also established a model of patient-derived skeletal muscle cells which express NCAM, myogenin, and MyHC by doxycycline-inducible overexpression of MyoD in DMD patient-derived hiPSCs [53]. Interestingly, MyoD-induced iPSCs also showed suppression of pluripotent genes such as Nanog and a transient increase in the gene expression levels of T (Brachyury T), Pax3, and Pax7, which belong to paraxial mesodermal/myogenic progenitor genes, upstream genes of myogenesis. It is possible that low levels of MyoD activity in hiPSCs may initially suppress their pluripotent state while failing to induce myogenic programs, which may result in transient paraxial mesodermal induction. Supporting this idea, BAF60C, a SWI/SNF component that is involved in chromatin remodeling and binds to MyoD, is required to induce full myogenic program in MyoD-overexpressing hESCs [54]. Overexpression of MyoD alone in hESC can only induce some paraxial mesodermal genes such as Brachyury T, mesogenin, and Mesp1 but not myogenic genes. Co-overexpression of MyoD and BAF60C was now able to induce myogenic program but not paraxial mesodermal gene expression, indicating that there are different epigenetic landscapes between pluripotent ESCs/iPSCs and differentiating ESC/iPSCs in which MyoD is more accessible to DNA targets than those in pluripotent cells. The authors then argued that without specific chromatin modifiers, only committed cells give rise to myogenic cells by MyoD. These results strongly indicate that nuclear landscapes are important for cell homogeneity for the specific cell differentiation in ESC/iPSC cultures. Similar observations were seen in overexpression of MyoD in P19 embryonal carcinoma stem cells, which can induce paraxial mesodermal genes including Meox1, Pax3, Pax7, Six1, and Eya2 followed by muscle-specific genes. However, these MyoD-induced paraxial mesodermal genes were mediated by direct MyoD binding to their regulatory regions, which was proven by chromatin immunoprecipitation (ChIP) assays, indicating the novel role for MyoD in paraxial mesodermal cell induction [55].

hESCs/iPSCs have been differentiated into myofibers by overexpression of MyoD, and this method is considered an excellent in vitro model for human skeletal muscle diseases for muscle functional tests, therapeutic drug screening, and genetic corrections such as exon skipping and DNA editing. Shoji et al. have shown that DMD patient-derived iPSCs were used for myogenic differentiation via PiggyBac-mediated MyoD overexpression. These myogenic cells were treated with morpholinos for exon-skipping strategies for dystrophin gene correction and showed muscle functional improvement [56]. Li et al. have shown that patient-derived hiPSC gene correction by TALEN and CRISPR-Cas9 systems, and these genetically corrected hiPSCs were used for myogenic differentiation via overexpression of MyoD [57]. This work also revealed that the TALEN and CRISPR-Cas9-mediated exon 44 knock-in approach in the dystrophin gene has high efficiency in gene-editing methods for DMD patient-derived cells in which the exon 44 is missing in the genome.

Along this line of the strategy, Darabi et al. first performed overexpression of Pax3 gene, which can be activated by treatment with doxycycline in mESCs, and showed efficient induction of MyoD/Myf5(+) skeletal myoblasts in EB cultures [15]. Upon removing doxycycline, these myogenic cells underwent MyHC(+) myotubes. However, teratoma formation was observed after EB cell transplantation into cardiotoxin-injured regenerating skeletal muscle in Rag2/:C/ immunodeficient mice [15]. This indicates that myogenic cell cultures induced by Pax3 in mESCs still contain some undifferentiated cells which gave rise to teratomas. To overcome this problem, the same authors separated paraxial mesodermal cells from Pax3-induced EB cells by FACS using antibodies against cell surface markers as PDGFR(+)Flk-1() cell populations. After cell sorting, isolated Pax3-induced paraxial mesodermal cells were successfully engrafted and contributed to regenerating muscle in mdx:Rag2/:C/ DMD model immunodeficient mice without any teratoma formations. Darabi et al. also showed successful myogenic induction in mESCs and hES/iPSCs by overexpression of Pax7 [58, 59]. Pax3 and Pax7 are not only expressed in myogenic progenitor cells. They are also expressed in neural tube and neural crest cell-derived cells including a part of cardiac cell types in developmental stage, suggesting that further purification to skeletal muscle cell lineage is crucial for therapeutic applications for muscle diseases including DMD.

Taken together, overexpression of myogenic master transcription factors such as MyoD or Pax3/Pax7 is an excellent strategy for myogenic induction in hESCs and hiPSCs, which can be utilized for in vitro muscle disease models for their functional test and drug screening. However, for the safe stem cell therapy, it is essential to maintain the good cellular and genetic qualities of hESC/hiPSC-derived myogenic cells before transplantation. Therefore, random integration sites of overexpression vectors for myogenic master transcription factors and inappropriate expression control of these transgenes may diminish the safety of using these induced myogenic cells for therapeutic stem cell transplantation.

Stepwise induction protocols utilizing small molecules and growth factors have been established as alternative myogenic induction approaches and a more applicable method for therapeutic situations. As described above, during embryonic myogenesis, somites and dermomyotomes receive secreted signals such as Wnts, Notch ligands, Shh, FGF, BMP, and retinoic acid (RA) with morphogen gradients from surrounding tissues in order to induce the formation of myogenic cells (Figure 2). The canonical Wnt signaling pathway has been shown to play essential roles in the development of myogenesis. In mouse embryogenesis, Wnt1 and Wnt3a secreted from the dorsal neural tube can promote myogenic differentiation of dorsomedial dermomyotome via activation of Myf5 [31, 32, 60]. Wnt3a is able to stabilize -catenin which associates with TCF/LEF transcription factors that bind to the enhancer region of Myf5 during myogenesis [61]. Other Wnt proteins, Wnt6 and Wnt7a, which emerge from the surface ectoderm, induce MyoD [62]. BMP functions as an inhibitor of myogenesis by suppression of some myogenic gene expressions. In the lateral mesoderm, BMP4 is able to increase Pax3 expression which delays Myf5 expression in order to maintain an undifferentiated myogenic progenitor state [63]. Therefore, Wnts and BMPs regulate myogenic development by antagonizing each other for myogenic transcription factor gene expression [64, 65]. Wnt also induces Noggin expression to antagonize BMP signals in the dorsomedial lip of the dermomyotome [66]. In this region, MyoD expression level is increased, which causes myotome formation. Notch signaling plays essential roles for cell-cell communication to specify the different cells in developmental stages. During myotome formation, Notch is expressed in dermomyotome, and Notch1 and Notch2 are expressed in dorsomedial lip of dermomyotome. Delta1, a Notch ligand, is expressed in neural crest cells which transiently interact with myogenic progenitor cells in dorsomedial lip of dermomyotome via Notch1 and 2. This contact induces expression of the Myf5 or MyoD gene in the myogenic progenitor cells followed by myotome formation. The loss of function of Delta1 in the neural crest displays delaying skeletal muscle formation [67]. Knockdown of Notch genes or use of a dominant-negative form of mastermind, a Notch transcriptional coactivator, clearly shows dramatically decrease of Myf5 and MyHC(+) myogenic cells. Interestingly, induction of Notch intracellular domain (NICD), a constitutive active form of Notch, can promote myogenesis, while continuous expression of NICD prevents terminal differentiation. Taken together, transient and timely activation of Notch is crucial for myotome formation from dermomyotome [30].

Current studies for myogenic differentiation of ESCs/iPSCs have utilized supplementation with some growth factors and small molecules, which would mimic the myogenic development described above in combination with embryoid body (EB) aggregation and FACS separation of mesodermal cells (Table 2). To induce paraxial mesoderm cells from mESCs, Sakurai et al. utilized BMP4 in serum-free cultures [68]. Three days after treatment with BMP4, mESCs could be differentiated into primitive streak mesodermal-like cells, but the continuous treatment with BMP4 turned the ESCs into osteogenic cells. Therefore, they used LiCl after treatment with BMP4 to enhance Wnt signaling, which is able to induce myogenic differentiation. After treatment with LiCl, PDGFR(+) E-cadherin() paraxial mesodermal cells were sorted by FACS. These sorted cells were cultured with IGF, HGF, and FGF for two weeks in order to induce myogenic differentiation. Hwang et al. have shown that treatment with Wnt3a efficiently promotes skeletal muscle differentiation of hESCs [69]. hESCs were cultured to form EB for 9 days followed by differentiation of EBs for additional 7 days, and then PDGFR(+) cells were sorted by FACS. These PDGFR(+) cells were cultured with Wnt3a for additional 14 days. Consequently, these Wnt3a-treated cells display significantly increased myogenic transcription factors and structural proteins at both mRNA and protein levels. An interesting approach to identify key molecules that induce myogenic cells was reported by Xu et al. [70]. They utilized reporter systems in zebrafish embryos to display myogenic progenitor cell induction and myogenic differentiation in order to identify small compounds for myogenic induction. Myf5-GFP marks myogenic progenitor cells, while myosin light polypeptide 2 (mylz2)-mCherry marks terminally differentiated muscle cells. They found that a mixed cocktail containing GSK3 inhibitor, bFGF, and forskolin has the potential to induce robust myogenic induction in hiPSCs. GSK3 inhibitors act as a canonical Wnt signaling activator via stabilizing -catenin protein, which is crucial for inducing mesodermal cells. Forskolin activates adenylyl cyclase, which then stimulates cAMP signaling. cAMP response element-binding protein (CREB) is able to stimulate cell proliferation of primary myoblasts in vitro, suggesting that the forskolin-cAMP-CREB pathway may help myogenic cell expansion [71], However the precise mechanisms for CREB-mediated myogenic cell expansion remain unclear. The adenylyl cyclase signaling cascade leads to CREB activation [71]. During embryogenesis, phosphorylated CREB has been found at dorsal somite and dermomyotome. CREB gene knockout mice display significantly decreased Myf5 and MyoD expressions in myotomes. While activation of Wnt1 or Wnt7a promotes Pax3, Myf5, and MyoD expressions, inhibition of CREB eliminates these Wnt-mediated myogenic gene expressions without altering the Wnt canonical pathway, suggesting that CREB-induced myogenic activation may be mediated through noncanonical Wnt pathways. Several groups also utilized GSK3 inhibitors for inducing mesodermal cells from ESCs and iPSCs [72, 73]. These mesodermal cell-like cells were expanded by treatment with bFGF, and then ITS (insulin/transferrin/selenite) or N2 medium were used to induce myogenic differentiation. Finally, bFGF is a stimulator for myogenic cell proliferation. Caron et al. demonstrated that hESCs treated with GSK3 inhibitor, ascorbic acid, Alk5 inhibitor, dexamethasone, EGF, and insulin generated around 80% of Pax3(+) myogenic precursor cells in 10 days [74]. Treatment with SB431542, an inhibitor of Alk4, 5, and 7, PDGF, bFGF, oncostatin, and IGF was able to induce these Pax3(+) myogenic precursor cells into around 5060% of MyoD(+) myoblasts in an additional 8 days. For the final step, treatment with insulin, necrosulfonamide, an inhibitor of necrosis, oncostatin, and ascorbic acid was able to induce these myoblasts into myotubes in an additional 8 days. Importantly, the same authors utilized ESCs from human facioscapulohumeral muscular dystrophy (FSHD) to demonstrate the myogenic characterization after myogenic induction by using the protocol described above. Hosoyama et al. have shown that hESCs/iPSCs with high concentrations of bFGF and EGF in combination with cell aggregation, termed EZ spheres, efficiently give rise to myogenic cells [75]. After 6-week culture, around 4050% of cells expressed Pax7, MyoD, or myogenin. However, the authors also showed that EZ spheres included around 30% of Tuj1(+) neural cells. Therefore, the authors discussed the utilization of molecules for activation of mesodermal and myogenic signaling pathways such as BMPs and Wnts.

Taken together, it is likely that the induced cell populations from ESCs/iPSCs may contain other cell types such as neural cells or cardiac cells because neural cells share similar transcription factor gene expression with myogenic cells such as Pax3, and cardiac cells also develop from mesodermal cells. To overcome this limitation, Chal et al. treated ESCs/iPSCs with BMP4 inhibitor, which prevents ESCs/iPSCs from differentiating into lateral mesodermal cells [76, 77]. To identify what genes are involved in myogenic differentiation in vivo, they performed a microarray analysis which compared samples of dissected fragments in mouse embryos, which are able to separate tail bud, presomitic mesoderm, and somite regions. From microarray data, the authors focused on Mesogenin1 (Msgn1) and Pax3 genes. Importantly, they utilized three lineage tracing reporters, Msgn1-repV (Mesogenin1-Venus) marking posterior somitic mesoderm, Pax3-GFP marking anterior somitic mesoderm and myogenic cells, and Myog-repV (Myogenin-Venus) marking differentiated myocytes, allowing the authors to readily detect different differentiation stages during ESC/iPSC cultures. Treatment with GSK3 inhibitors and then BMP inhibitors in ESC cultures induced Msgn1(+) somitic mesoderm with 45 to 65% efficiencies, Pax3(+) anterior somitic mesoderm with 30 to 50% efficiencies, and myogenin(+) myogenic cells with 25 to 30% efficiencies. Furthermore, the authors examined differentiation of mdx ESCs into skeletal muscle cells and revealed abnormal branching myofibers. Current protocols were also published and described more details for hiPSC differentiation [77].

Some nonmuscle cell populations such as mesoangioblasts have the potential to differentiate into skeletal muscle [6]. Mesoangioblasts were originally isolated from embryonic mouse dorsal aorta as vessel-associated pericyte-like cells, which have the ability to differentiate into a myogenic lineage in vitro and in vivo [6, 78]. Mesoangioblasts possess an advantage for the clinical cell-based treatment because they can be injected through an intra-arterial route to systemically deliver cells, which is crucial for therapeutic cell transplantation for muscular dystrophies [79]. Tedesco et al. successfully generated human iPSC-derived mesoangioblast-like stem/progenitor cells called HIDEMs by stepwise protocols without FACS sorting [80, 81]. They displayed similar gene expression profiles as embryonic mesoangioblasts. However, HIDEMs do not spontaneously differentiate into skeletal muscle cells, and thus, the authors utilized overexpression of MyoD to differentiate into skeletal muscle cells. Similar to mesoangioblasts, HIDEM-derived myogenic cells could be delivered to injured muscle via intramuscular and intra-arterial routes. Furthermore, HIDEMs have been generated from hiPSCs derived from limb-girdle muscular dystrophy (LGMD) type 2D patients and used for gene correction and cell transplantation experiments for the potential therapeutic application.

Myogenic precursor cells derived from ESCs/iPSCs by various methods may contain nonmuscle cells. Therefore, further purification is mandatory for therapeutic applications. Barberi et al. isolated CD73(+) multipotent mesenchymal precursor cells from hESCs by FACS, and these cells underwent differentiation into fat, cartilage, bone, and skeletal muscle cells [82]. Barberi et al. also demonstrated that hESCs cultured on OP9 stroma cells generated around 5% of CD73(+) adult mesenchymal stem cell-like cells [83]. After FACS, these CD73(+) mesenchymal stem cell-like cells were cultured with ITS medium for 4 weeks and then gave rise to NCAM(+) myogenic cells. After FACS sorting, these NCAM(+) myogenic cells were purified by FACS and transplanted into immunodeficient mice to show their myogenic contribution to regenerating muscle.

It has been shown that many genes are associated with myogenesis. In addition, exhaustive analysis, such as microarray, RNA-seq, and single cell RNA-seq supplies much gene information in many different stages. Chal et al. showed key signaling factors by microarray from presomitic somite, somite, and tail bud cells [76]. They found that initial Wnt signaling has important roles for somite differentiation. Furthermore, mapping differentiated hESCs by single cell RNA-seq analysis is useful to characterize each differentiated stage [84].

As shown above, cell sorting of mesodermal progenitor cells, mesenchymal precursor cells, or myogenic cells is a powerful tool to obtain pure myogenic populations from differentiated pluripotent cells. Sakurai et al. have been able to induce PDGFR(+)Flk-1() mesodermal progenitor cells by FACS followed by myogenic differentiation [85]. Chang et al. and Mizuno et al. have been able to sort SMC-2.6(+) myogenic cells from mouse ESCs/iPSCs [86, 87]. These SMC-2.6(+) myogenic cells were successfully engrafted into mouse regenerating skeletal muscle. However, this SMC-2.6 antibody only recognizes mouse myogenic cells but not human myogenic cells [86, 88]. Therefore, Borchin et al. have shown that hiPSC-derived myogenic cells differentiated into c-met(+)CXCR4(+)ACHR(+) cells, displaying that over 95% of sorted cells are Pax7(+) myogenic cells [72]. Taken together, current myogenic induction protocols utilizing small molecules and growth factors, with or without myogenic transcription factors, have been largely improved in the last 5 years. It is crucial to standardize the induction protocols in the near future to obtain sufficient myogenic cell conversion from pluripotent stem cells.

Recent work demonstrated that cells inherit a stable genetic program partly through various epigenetic marks, such as DNA methylation and histone modifications. This cellular memory needs to be erased during genetic reprogramming, and the cellular program reverted to that of an earlier developmental stage [16, 22, 89]. However, iPSCs retaining an epigenetic memory of their origin can readily differentiate into their original tissues [1619, 90100]. This phenomenon becomes a double-edged sword for the reprogramming process since the retention of epigenetic memory may reduce the quality of pluripotency while increasing the differentiation efficiency into their original tissues. DNA methylation levels are relatively low in the pluripotent stem cells compared to the high levels of DNA methylation seen in somatic cells [101]. Global DNA demethylation is required for the reprogramming process [102]. In the context of these observations, recent work demonstrates that activation-induced cytidine deaminase AID/AICDA contributing to the DNA demethylation can stabilize stem-cell phenotypes by removing epigenetic memory of pluripotent genes. This directly deaminates 5-methylcytosine in concert with base-excision repair to exchange cytosine in genomic DNA [103]. MicroRNA-155 has been identified as a key player for the retention of epigenetic memory during in vitro differentiation of hematopoietic progenitor cell-derived iPSCs toward hematopoietic progenitors [104]. iPSCs that maintained high levels of miR-155 expression tend to differentiate into the original somatic population more efficiently.

Recently, we generated murine skeletal muscle cell-derived iPSCs (myoblast-derived iPSCs) [23] and compared the efficiency of differentiation of myogenic progenitor cells between myoblast-derived iPSCs and fibroblast-derived iPSCs. After EB cultures, more satellite cell/myogenic progenitor cell differentiation occurred in myoblast-derived iPSCs than that in fibroblast-derived-iPSCs (unpublished observation and Figure 3), suggesting that myoblast-derived iPSCs are potential myogenic and satellite cell sources for DMD and other muscular dystrophy therapies (Figure 4). We also noticed that MyoD gene suppression by Oct4 is required for reprogramming in myoblasts to produce iPSCs (Figure 3) [23]. During overexpression of Oct4, Oct4 first binds to the Oct4 consensus sequence located in two MyoD enhancers (a core enhancer and distal regulatory region) [105107] preceding occupancy at the promoter in myoblasts in order to suppress MyoD gene expression. Interestingly, Oct4 binding to the MyoD core enhancer allows for establishment of a bivalent state in MyoD promoter as a poised state, marked by active (H3K4me3) and repressive (H3K27me3) modifications in fibroblasts, one of the characteristics of stem cells (Figure 3) [23, 108]. It should be investigated whether the similar bivalent state is also established in Oct4-expressing myoblasts during reprogramming process from myoblasts to pluripotent stem cells. It remains to be elucidated whether Oct4-mediated myogenic repression only relies on repression of MyoD expression or is just a general phenomenon of functional antagonism between Oct4 and MyoD on activation of muscle genes. Nevertheless, myoblast-derived iPSCs will enable us to produce an unlimited number of myogenic cells, including satellite cells that could form the basis of novel treatments for DMD and other muscular dystrophies (Figure 4).

There are pros and cons of transgene-free small molecule-mediated myogenic induction protocols. In the transgene-mediated induction protocols, integration of the transgene in the host genome may lead to risk for insertional mutagenesis. To circumvent this issue, there is an obvious advantage for transgene-free induction protocols. Some key molecules such as Wnt, FGF, and BMP have used signaling pathways to induce myogenic differentiation of ES/iPSCs. However, these molecules are also involved in induction of other types of cell lineages, which makes it difficult for ES/iPSCs to induce pure myogenic cell populations in vitro. By contrast, transgene-mediated myogenic induction is able to dictate desired specific cell lineages. In any case, it is necessary to intensively investigate these myogenic induction protocols for the efficient and safe stem cell therapy for patients.

For skeletal muscle diseases, patient-derived hiPSCs, which possess the ability to differentiate into myogenic progenitor cells followed by myotubes, can be a useful tool for drug screening and personalized medicine in clinical practice. However, there are still limitations for utilizing hiPSC-derived myogenic cells for regenerative medicine. For cell-based transplantation therapies such as a clinical situation, animal-free defined medium is essential for stem cell culture and skeletal muscle cell differentiation. Therefore, such animal-free defined medium needs to be established for optimal myogenic differentiation from hiPSCs. Gene correction in DMD patient iPSCs by TALENs and CRISPR-Cas9 systems are promising therapeutic approaches for stem cell transplantation. However, there are still problems for DNA-editing-mediated stem cell therapy such as safety and efficacy. Since iPSC-derived differentiated myotubes do not proliferate, they are not suited for cell transplantation. Therefore, a proper culture method needs to be established for hiPSCs in order to maintain cells in proliferating the myogenic precursor cell stage in vitro in order to expand cells to large quantities of transplantable cells for DMD and other muscular dystrophies. For other issues, it is essential to establish methods to separate ES/iPSC-derived pure skeletal muscle precursor cells from other cell types for safe stem cell therapy that excludes tumorigenic risks of contamination with undifferentiated cells. In the near future, these obstacles will be taken away for more efficient and safe stem cell therapy for DMD and other muscular dystrophies.

The authors declare that they have no conflicts of interest.

This work was supported by the NIH R01 (1R01AR062142) and NIH R21 (1R21AR070319). The authors thank Conor Burke-Smith and Neeladri Chowdhury for critical reading.

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Skeletal Muscle Cell Induction from Pluripotent Stem Cells

Cardiac Stem Cells Comments Off on Skeletal Muscle Cell Induction from Pluripotent Stem Cells | December 1st, 2022

Specific location in the body containing stem cells

Stem-cell niche refers to a microenvironment, within the specific anatomic location where stem cells are found, which interacts with stem cells to regulate cell fate.[1] The word 'niche' can be in reference to the in vivo or in vitro stem-cell microenvironment. During embryonic development, various niche factors act on embryonic stem cells to alter gene expression, and induce their proliferation or differentiation for the development of the fetus. Within the human body, stem-cell niches maintain adult stem cells in a quiescent state, but after tissue injury, the surrounding micro-environment actively signals to stem cells to promote either self-renewal or differentiation to form new tissues. Several factors are important to regulate stem-cell characteristics within the niche: cellcell interactions between stem cells, as well as interactions between stem cells and neighbouring differentiated cells, interactions between stem cells and adhesion molecules, extracellular matrix components, the oxygen tension, growth factors, cytokines, and the physicochemical nature of the environment including the pH, ionic strength (e.g. Ca2+ concentration) and metabolites, like ATP, are also important.[2] The stem cells and niche may induce each other during development and reciprocally signal to maintain each other during adulthood.

Scientists are studying the various components of the niche and trying to replicate the in vivo niche conditions in vitro.[2] This is because for regenerative therapies, cell proliferation and differentiation must be controlled in flasks or plates, so that sufficient quantity of the proper cell type are produced prior to being introduced back into the patient for therapy.

Human embryonic stem cells are often grown in fibroblastic growth factor-2 containing, fetal bovine serum supplemented media. They are grown on a feeder layer of cells, which is believed to be supportive in maintaining the pluripotent characteristics of embryonic stem cells. However, even these conditions may not truly mimic in vivo niche conditions.

Adult stem cells remain in an undifferentiated state throughout adult life. However, when they are cultured in vitro, they often undergo an 'aging' process in which their morphology is changed and their proliferative capacity is decreased. It is believed that correct culturing conditions of adult stem cells needs to be improved so that adult stem cells can maintain their stemness over time.[citation needed]

A Nature Insight review defines niche as follows:

"Stem-cell populations are established in 'niches' specific anatomic locations that regulate how they participate in tissue generation, maintenance and repair. The niche saves stem cells from depletion, while protecting the host from over-exuberant stem-cell proliferation. It constitutes a basic unit of tissue physiology, integrating signals that mediate the balanced response of stem cells to the needs of organisms. Yet the niche may also induce pathologies by imposing aberrant function on stem cells or other targets. The interplay between stem cells and their niche creates the dynamic system necessary for sustaining tissues, and for the ultimate design of stem-cell therapeutics ... The simple location of stem cells is not sufficient to define a niche. The niche must have both anatomic and functional dimensions."[3]

Though the concept of stem cell niche was prevailing in vertebrates, the first characterization of stem cell niche in vivo was worked out in Drosophila germinal development.

By continuous intravital imaging in mice, researchers were able to explore the structure of the stem cell niche and to obtain the fate of individual stem cells (SCs) and their progeny over time in vivo. In particular in intestinal crypt,[4] two distinct groups of SCs have been identified: the "border stem cells" located in the upper part of the niche at the interface with transit amplifying cells (TAs), and "central stem cells" located at the crypt base. The proliferative potential of the two groups was unequal and correlated with the cells' location (central or border). It was also shown that the two SC compartments acted in accord to maintain a constant cell population and a steady cellular turnover. A similar dependence of self-renewal potential on proximity to the niche border was reported in the context of hair follicle, in an in vivo live-imaging study.[5]

This bi-compartmental structure of stem cell niche has been mathematically modeled to obtain the optimal architecture that leads to the maximum delay in double-hit mutant production.[6] They found that the bi-compartmental SC architecture minimizes the rate of two-hit mutant production compared to the single SC compartment model. Moreover, the minimum probability of double-hit mutant generation corresponds to purely symmetric division of SCs with a large proliferation rate of border stem cells along with a small, but non-zero, proliferation rate of central stem cells.[citation needed]

Stem cell niches harboring continuously dividing cells, such as those located at the base of the intestinal gland, are maintained at small population size. This presents a challenge to the maintenance of multicellular tissues, as small populations of asexually dividing individuals will accumulate deleterious mutations through genetic drift and succumb to mutational meltdown.[7] Mathematical modeling of the intestinal gland reveals that the small population size within the stem cell niche minimizes the probability of carcinogenesis occurring anywhere, at the expense of gradually accumulated deleterious mutations throughout organismal lifetimea process that contributes to tissue degradation and aging.[8] Therefore, the population size of the stem cell niche represents an evolutionary trade-off between the probability of cancer formation and the rate of aging.

Germline stem cells (GSCs) are found in organisms that continuously produce sperm and eggs until they are sterile. These specialized stem cells reside in the GSC niche, the initial site for gamete production, which is composed of the GSCs, somatic stem cells, and other somatic cells. In particular, the GSC niche is well studied in the genetic model organism Drosophila melanogaster and has provided an extensive understanding of the molecular basis of stem cell regulation.[citation needed]

In Drosophila melanogaster, the GSC niche resides in the anterior-most region of each ovariole, known as the germarium. The GSC niche consists of necessary somatic cells-terminal filament cells, cap cells, escort cells, and other stem cells which function to maintain the GSCs.[9] The GSC niche holds on average 23 GSCs, which are directly attached to somatic cap cells and Escort stem cells, which send maintenance signals directly to the GSCs.[10] GSCs are easily identified through histological staining against vasa protein (to identify germ cells) and 1B1 protein (to outline cell structures and a germline specific fusome structure). Their physical attachment to the cap cells is necessary for their maintenance and activity.[10] A GSC will divide asymmetrically to produce one daughter cystoblast, which then undergoes 4 rounds of incomplete mitosis as it progresses down the ovariole (through the process of oogenesis) eventually emerging as a mature egg chamber; the fusome found in the GSCs functions in cyst formation and may regulate asymmetrical cell divisions of the GSCs.[11] Because of the abundant genetic tools available for use in Drosophila melanogaster and the ease of detecting GSCs through histological stainings, researchers have uncovered several molecular pathways controlling GSC maintenance and activity.[12] [13]

The Bone Morphogenetic Protein (BMP) ligands Decapentaplegic (Dpp) and Glass-bottom-boat (Gbb) ligand are directly signalled to the GSCs, and are essential for GSC maintenance and self-renewal.[14] BMP signalling in the niche functions to directly repress expression of Bag-of-marbles (Bam) in GSCs, which is up-regulated in developing cystoblast cells.[15] Loss of function of dpp in the niche results in de-repression of Bam in GSCs, resulting in rapid differentiation of the GSCs.[10] Along with BMP signalling, cap cells also signal other molecules to GSCs: Yb and Piwi. Both of these molecules are required non-autonomously to the GSCs for proliferation-piwi is also required autonomously in the GSCs for proliferation.[16] In the germarium, BMP signaling has a short-range effect, therefore the physical attachment of GSCs to cap cells is important for maintenance and activity.[citation needed]

The GSCs are physically attached to the cap cells by Drosophila E-cadherin (DE-cadherin) adherens junctions and if this physical attachment is lost GSCs will differentiate and lose their identity as a stem cell.[10] The gene encoding DE-cadherin, shotgun (shg), and a gene encoding Beta-catenin ortholog, armadillo, control this physical attachment.[17] A GTPase molecule, rab11, is involved in cell trafficking of DE-cadherins. Knocking out rab11 in GSCs results in detachment of GSCs from the cap cells and premature differentiation of GSCs.[18] Additionally, zero population growth (zpg), encoding a germline-specific gap junction is required for germ cell differentiation.[19]

Both diet and insulin-like signaling directly control GSC proliferation in Drosophila melanogaster. Increasing levels of Drosophila insulin-like peptide (DILP) through diet results in increased GSC proliferation.[20] Up-regulation of DILPs in aged GSCs and their niche results in increased maintenance and proliferation.[21] It has also been shown that DILPs regulate cap cell quantities and regulate the physical attachment of GSCs to cap cells.[21]

There are two possible mechanisms for stem cell renewal, symmetrical GSC division or de-differentiation of cystoblasts. Normally, GSCs will divide asymmetrically to produce one daughter cystoblast, but it has been proposed that symmetrical division could result in the two daughter cells remaining GSCs.[22][23] If GSCs are ablated to create an empty niche and the cap cells are still present and sending maintenance signals, differentiated cystoblasts can be recruited to the niche and de-differentiate into functional GSCs.[24]

As the Drosophila female ages, the stem cell niche undergoes age-dependent loss of GSC presence and activity. These losses are thought to be caused in part by degradation of the important signaling factors from the niche that maintains GSCs and their activity. Progressive decline in GSC activity contributes to the observed reduction in fecundity of Drosophila melanogaster at old age; this decline in GSC activity can be partially attributed to a reduction of signaling pathway activity in the GSC niche.[25][26] It has been found that there is a reduction in Dpp and Gbb signaling through aging. In addition to a reduction in niche signaling pathway activity, GSCs age cell-autonomously. In addition to studying the decline of signals coming from the niche, GSCs age intrinsically; there is age-dependent reduction of adhesion of GSCs to the cap cells and there is accumulation of Reactive Oxygen species (ROS) resulting in cellular damage which contributes to GSC aging. There is an observed reduction in the number of cap cells and the physical attachment of GSCs to cap cells through aging. Shg is expressed at significantly lower levels in an old GSC niche in comparison to a young one.[26]

Males of Drosophila melanogaster each have two testes long, tubular, coiled structures and at the anterior most tip of each lies the GSC niche. The testis GSC niche is built around a population of non-mitotic hub cells (a.k.a. niche cells), to which two populations of stem cells adhere: the GSCs and the somatic stem cells (SSCs, a.k.a. somatic cyst stem cells/cyst stem cells). Each GSC is enclosed by a pair of SSCs, though each stem cell type is still in contact with the hub cells. In this way, the stem cell niche consists of these three cell types, as not only do the hub cells regulate GSC and SSC behaviour, but the stem cells also regulate the activity of each other. The Drosophila testis GSC niche has proven a valuable model system for examining a wide range of cellular processes and signalling pathways.[27]

The process of spermatogenesis begins when the GSCs divide asymmetrically, producing a GSC that maintains hub contact, and a gonialblast that exits the niche. The SSCs divide with their GSC partner, and their non-mitotic progeny, the somatic cyst cells (SCCs, a.k.a. cyst cells) will enclose the gonialblast. The gonialblast then undergoes four rounds of synchronous, transit-amplifying divisions with incomplete cytokinesis to produce a sixteen-cell spermatogonial cyst. This spermatogonial cyst then differentiates and grows into a spermatocyte, which will eventually undergo meiosis and produce sperm.[27]

The two main molecular signalling pathways regulating stem cell behaviour in the testis GSC niche are the Jak-STAT and BMP signalling pathways. Jak-STAT signalling originates in the hub cells, where the ligand Upd is secreted to the GSCs and SSCs.[28][29] This leads to activation of the Drosophila STAT, Stat92E, a transcription factor which effects GSC adhesion to the hub cells,[30] and SSC self-renewal via Zfh-1.[31] Jak-STAT signalling also influences the activation of BMP signalling, via the ligands Dpp and Gbb. These ligands are secreted into the GSCs from the SSCs and hub cells, activate BMP signalling, and suppress the expression of Bam, a differentiation factor.[32] Outside of the niche, gonialblasts no longer receive BMP ligands, and are free to begin their differentiation program. Other important signalling pathways include the MAPK and Hedgehog, which regulate germline enclosure [33] and somatic cell self-renewal,[34] respectively.

The murine GSC niche in males, also called spermatogonial stem cell (SSC) niche, is located in the basal region of seminiferous tubules in the testes. The seminiferous epithelium is composed of sertoli cells that are in contact with the basement membrane of the tubules, which separates the sertoli cells from the interstitial tissue below. This interstitial tissue comprises Leydig cells, macrophages, mesenchymal cells, capillary networks, and nerves.[35]

During development, primordial germ cells migrate into the seminiferous tubules and downward towards the basement membrane whilst remaining attached to the sertoli cells where they will subsequently differentiate into SSCs, also referred to as Asingle spermatogonia.[35][36] These SSCs can either self-renew or commit to differentiating into spermatozoa upon the proliferation of Asingle into Apaired spermatogonia. The 2 cells of Apaired spermatogonia remain attached by intercellular bridges and subsequently divide into Aaligned spermatogonia, which is made up of 416 connected cells. Aaligned spermatogonia then undergo meiosis I to form spermatocytes and meiosis II to form spermatids which will mature into spermatozoa.[37][38] This differentiation occurs along the longitudinal axis of sertoli cells, from the basement membrane to the apical lumen of the seminiferous tubules. However, sertoli cells form tight junctions that separate SSCs and spermatogonia in contact with the basement membrane from the spermatocytes and spermatids to create a basal and an adluminal compartment, whereby differentiating spermatocytes must traverse the tight junctions.[35][39] These tight junctions form the blood testis barrier (BTB) and have been suggested to play a role in isolating differentiated cells in the adluminal compartment from secreted factors by the interstitial tissue and vasculature neighboring the basal compartment.[35]

The basement membrane of the seminiferous tubule is a modified form of extracellular matrix composed of fibronectin, collagens, and laminin.[35] 1- integrin is expressed on the surface of SSCs and is involved in their adhesion to the laminin component of the basement membrane although other adhesion molecules are likely also implicated in the attachment of SSCs to the basement membrane.[40] E cadherin expression on SSCs in mice, unlike in Drosophila, have been shown to be dispensable as the transplantation of cultured SSCs lacking E-cadherin are able to colonize host seminiferous tubules and undergo spermatogenesis.[41] In addition the blood testis barrier provides architectural support and is composed of tight junction components such as occludins, claudins and zonula occludens (ZOs) which show dynamic expression during spermatogenesis.[42] For example, claudin 11 has been shown to be a necessary component of these tight junctions as mice lacking this gene have a defective blood testis barrier and do not produce mature spermatozoa.[40]

GDNF (Glial cell-derived neurotrophic factor) is known to stimulate self-renewal of SSCs and is secreted by the sertoli cells under the influence of gonadotropin FSH. GDNF is a related member of the TGF superfamily of growth factors and when overexpressed in mice, an increase in undifferentiated spermatogonia was observed which led to the formation of germ tumours.[35][40] In corroboration for its role as a renewal factor, heterozygous knockout male mice for GDNF show decreased spermatogenesis that eventually leads to infertility.[40] In addition the supplementation of GDNF has been shown to extend the expansion of mouse SSCs in culture. However, the GDNF receptor c-RET and co-receptor GFRa1 are not solely expressed on the SSCs but also on Apaired and Aaligned, therefore showing that GDNF is a renewal factor for Asingle to Aaligned in general rather than being specific to the Asingle SSC population. FGF2 (Fibroblast growth factor 2), secreted by sertoli cells, has also been shown to influence the renewal of SSCs and undifferentiated spermatogonia in a similar manner to GDNF.[35]

Although sertoli cells appear to play a major role in renewal, it expresses receptors for testosterone that is secreted by Leydig cells whereas germ cells do not contain this receptor- thus alluding to an important role of Leydig cells upstream in mediating renewal. Leydig cells also produce CSF 1 (Colony stimulating factor 1) for which SSCs strongly express the receptor CSF1R.[37] When CSF 1 was added in culture with GDNF and FGF2 no further increase in proliferation was observed, however, the longer the germ cells remained in culture with CSF-1 the greater the SSC density observed when these germ cells were transplanted into host seminiferous tubules. This showed CSF 1 to be a specific renewal factor that tilts the SSCs towards renewal over differentiation, rather than affecting proliferation of SSCs and spermatogonia. GDNF, FGF 2 and CSF 1 have also been shown to influence self-renewal of stem cells in other mammalian tissues.[35]

Plzf (Promyelocytic leukaemia zinc finger) has also been implicated in regulating SSC self-renewal and is expressed by Asingle, Apaired and Aaligned spermatogonia. Plzf directly inhibits the transcription of a receptor, c-kit, in these early spermatogonia. However, its absence in late spermatogonia permits c-kit expression, which is subsequently activated by its ligand SCF (stem cell factor) secreted by sertoli cells, resulting in further differentiation. Also, the addition of BMP4 and Activin-A have shown to reduce self-renewal of SSCs in culture and increase stem cell differentiation, with BMP4 shown to increase the expression of c-kit.[37]

Prolonged spermatogenesis relies on the maintenance of SSCs, however, this maintenance declines with age and leads to infertility. Mice between 12 and 14 months of age show decreased testis weight, reduced spermatogenesis and SSC content. Although stem cells are regarded as having the potential to infinitely replicate in vitro, factors provided by the niche are crucial in vivo. Indeed, serial transplantation of SSCs from male mice of different ages into young mice 3 months of age, whose endogenous spermatogenesis had been ablated, was used to estimate stem cell content given that each stem cell would generate a colony of spermatogenesis.[35][43] The results of this experiment showed that transplanted SSCs could be maintained far longer than their replicative lifespan for their age. In addition, a study also showed that SSCs from young fertile mice could not be maintained nor undergo spermatogenesis when transplanted into testes of old, infertile mice. Together, these results points towards a deterioration of the SSC niche itself with aging rather than the loss of intrinsic factors in the SSC.[43]

Vertebrate hematopoietic stem cells niche in the bone marrow is formed by cells subendosteal osteoblasts, sinusoidal endothelial cells and bone marrow stromal (also sometimes called reticular) cells which includes a mix of fibroblastoid, monocytic and adipocytic cells (which comprise marrow adipose tissue).[1]

The hair follicle stem cell niche is one of the more closely studied niches thanks to its relative accessibility and role in important diseases such as melanoma. The bulge area at the junction of arrector pili muscle to the hair follicle sheath has been shown to host the skin stem cells which can contribute to all epithelial skin layers. There cells are maintained by signaling in concert with niche cells signals include paracrine (e.g. sonic hedgehog), autocrine and juxtacrine signals.[44] The bulge region of the hair follicle relies on these signals to maintain the stemness of the cells. Fate mapping or cell lineage tracing has shown that Keratin 15 positive stem cells' progeny participate in all epithelial lineages.[45] The follicle undergoes cyclic regeneration in which these stem cells migrate to various regions and differentiate into the appropriate epithelial cell type. Some important signals in the hair follicle stem cell niche produced by the mesenchymal dermal papilla or the bulge include BMP, TGF- and Fibroblast growth factor (FGF) ligands and Wnt inhibitors.[46] While, Wnt signaling pathways and -catenin are important for stem cell maintenance,[47] over-expression of -catenin in hair follicles induces improper hair growth. Therefore, these signals such as Wnt inhibitors produced by surrounding cells are important to maintain and facilitate the stem cell niche.[48]

Intestinal organoids have been used to study intestinal stem cell niches. An intestinal organoid culture can be used to indirectly assess the effect of the manipulation on the stem cells through assessing the organoid's survival and growth. Research using intestinal organoids have demonstrated that the survival of intestinal stem cells is improved by the presence of neurons and fibroblasts,[49] and through the administration of IL-22.[50]

Cardiovascular stem cell niches can be found within the right ventricular free wall, atria and outflow tracks of the heart. They are composed of Isl1+/Flk1+ cardiac progenitor cells (CPCs) that are localized into discrete clusters within a ColIV and laminin extracellular matrix (ECM). ColI and fibronectin are predominantly found outside the CPC clusters within the myocardium. Immunohistochemical staining has been used to demonstrate that differentiating CPCs, which migrate away from the progenitor clusters and into the ColI and fibronectin ECM surrounding the niche, down-regulate Isl1 while up-regulating mature cardiac markers such as troponin C.[51] There is a current controversy over the role of Isl1+ cells in the cardiovascular system. While major publications have identified these cells as CPC's and have found a very large number in the murine and human heart, recent publications have found very few Isl1+ cells in the murine fetal heart and attribute their localization to the sinoatrial node,[52] which is known as an area that contributes to heart pacemaking. The role of these cells and their niche are under intense research and debate.[citation needed]

Neural stem cell niches are divided in two: the Subependymal zone (SEZ) and the Subgranular zone (SGZ).

The SEZ is a thin area beneath the ependymal cell layer that contains three types of neural stem cells: infrequently dividing neural stem cells (NSCs), rapidly dividing transit amplifying precursors (TaPs) and neuroblasts (NBs). The SEZ extracellular matrix (ECM) has significant differences in composition compared to surrounding tissues. Recently, it was described that progenitor cells, NSCs, TaPs and NBs were attached to ECM structures called Fractones.[53] These structures are rich in laminin, collagen and heparan sulfate proteoglycans.[54] Other ECM molecules, such as tenascin-C, MMPs and different proteoglycans are also implicated in the neural stem cell niche.[55]

Cancer tissue is morphologically heterogenous, not only due to the variety of cell types present, endothelial, fibroblast and various immune cells, but cancer cells themselves are not a homogenous population either.[citation needed]

In accordance with the hierarchy model of tumours, the cancer stem cells (CSC) are maintained by biochemical and physical contextual signals emanating from the microenvironment, called the cancer stem cell niche.[56] The CSC niche is very similar to normal stem cells niche (embryonic stem cell (ESC), Adult Stem Cell ASC) in function (maintaining of self-renewal, undifferentiated state and ability to differentiate) and in signalling pathways (Activin/Noda, Akt/PTEN, JAK/STAT, PI3-K, TGF-, Wnt and BMP).[57] It is hypothesized that CSCs arise form aberrant signalling of the microenvironment and participates not only in providing survival signals to CSCs but also in metastasis by induction of epithelial-mesenchymal transition (EMT).[citation needed]

Hypoxic condition in stem cell niches (ESC, ASC or CSC) is necessary for maintaining stem cells in an undifferentiated state and also for minimizing DNA damage via oxidation. The maintaining of the hypoxic state is under control of Hypoxia-Inducible transcription Factors (HIFs).[58] HIFs contribute to tumour progression, cell survival and metastasis by regulation of target genes as VEGF, GLUT-1, ADAM-1, Oct4 and Notch.[57]

Hypoxia plays an important role in the regulation of cancer stem cell niches and EMT through the promotion of HIFs.[59] These HIFs help maintain cancer stem cell niches by regulating important stemness genes such as Oct4, Nanog, SOX2, Klf4, and cMyc.[60][61] HIFs also regulate important tumor suppressor genes such as p53 and genes that promote metastasis.[62][63] Although HIFs increase the survival of cells by decreasing the effects of oxidative stress, they have also been shown to decrease factors such as RAD51 and H2AX that maintain genomic stability.[64] In the hypoxic condition there is an increase of intracellular Reactive Oxygen Species (ROS) which also promote CSCs survival via stress response.[65][66] ROS stabilizes HIF-1 which promotes the Met proto-oncogene, which drives metastasis or motogenic escape in melanoma cells.[67] All of these factors contribute to a cancer stem cell phenotype which is why it is often referred to as a hypoxic stem cell niche. Hypoxic environments are often found in tumors where the cells are dividing faster that angiogenesis can occur. It is important to study hypoxia as an aspect of cancer because hypoxic environments have been shown to be resistant to radiation therapy.[68] Radiation has been shown to increase the amounts of HIF-1.[69] EMT induction by hypoxia though interactions between HIF-1 and ROS is crucial for metastasis in cancers such as melanoma. It has been found that many genes associated with melanoma are regulated by hypoxia such as MXI1, FN1, and NME1.[70]

Epithelialmesenchymal transition is a morphogenetic process, normally occurs in embryogenesis that is "hijacked" by cancer stem cells by detaching from their primary place and migrating to another one. The dissemination is followed by reverse transition so-called Epithelial-Mesenchymal Transition (EMT). This process is regulated by CSCs microenvironment via the same signalling pathways as in embryogenesis using the growth factors (TGF-, PDGF, EGF), cytokine IL-8 and extracellular matrix components. These growth factors' interactions through intracellular signal transducers like -catenin has been shown to induce metastatic potential.[71][72] A characteristic of EMT is loss of the epithelial markers (E-cadherin, cytokeratins, claudin, occluding, desmoglein, desmocolin) and gain of mesenchymal markers (N-cadherin, vimentin, fibronectin).[73]

There is also certain degree of similarity in homing-mobilization of normal stem cells and metastasis-invasion of cancer stem cells. There is an important role of Matrix MetalloProteinases (MMP), the principal extracellular matrix degrading enzymes, thus for example matrix metalloproteinase-2 and 9 are induced to expression and secretion by stromal cells during metastasis of colon cancer via direct contact or paracrine regulation. The next sharing molecule is Stromal cell-Derived Factor-1 (SDF-1).[73][74]

The EMT and cancer progression can be triggered also by chronic inflammation. The main roles have molecules (IL-6, IL-8, TNF-, NFB, TGF-, HIF-1) which can regulate both processes through regulation of downstream signalling that overlapping between EMT and inflammation.[57] The downstream pathways involving in regulation of CSCs are Wnt, SHH, Notch, TGF-, RTKs-EGF, FGF, IGF, HGF.

NFB regulates the EMT, migration and invasion of CSCs through Slug, Snail and Twist. The activation of NFB leads to increase not only in production of IL-6, TNF- and SDF-1 but also in delivery of growth factors.

The source of the cytokine production are lymphocytes (TNF-), Mesenchymal Stem Cells (SDF-1, IL-6, IL8).

Interleukin 6 mediates activation of STAT3. The high level of STAT3 was described in isolated CSCs from liver, bone, cervical and brain cancer. The inhibition of STAT3 results in dramatic reduction in their formation. Generally IL-6 contributes a survival advantage to local stem cells and thus facilitates tumorigenesis.[57]

SDF-1 secreted from Mesenchymal Stem Cells (MSCs) has important role in homing and maintenance of Hematopoietic Stem Cell (HSC) in bone marrow niche but also in homing and dissemination of CSC.[74]

Hypoxia is a main stimulant for angiogenesis, with HIF-1 being the primary mediator. Angiogenesis induced by hypoxic conditions is called an "Angiogenic switch". HIF-1 promotes expression of several angiogenic factors: Vascular Endothelial Growth Factor (VEGF), basic Fibroblast Growth Factor (bFGF), Placenta-Like Growth Factor (PLGF), Platelet-Derived Growth Factor (PDGF) and Epidermal Growth Factor. But there is evidence that the expression of angiogenic agens by cancer cells can also be HIF-1 independent. It seems that there is an important role of Ras protein, and that intracellular levels of calcium regulate the expression of angiogenic genes in response to hypoxia.[73]

The angiogenic switch downregulates angiogenesis suppressor proteins, such as thrombospondin, angiostatin, endostatin and tumstatin. Angiogenesis is necessary for the primary tumour growth.[citation needed]

During injury, support cells are able to activate a program for repair, recapitulating aspects of development in the area of damage. These areas become permissive for stem cell renewal, migration and differentiation. For instance in the CNS, injury is able to activate a developmental program in astrocytes that allow them to express molecules that support stem cells such as chemokines i.e. SDF-1[75] and morphogens such as sonic hedgehog.[76]

It is evident that biophysio-chemical characteristics of ECM such as composition, shape, topography, stiffness, and mechanical strength can control the stem cell behavior. These ECM factors are equally important when stem cells are grown in vitro. Given a choice between niche cell-stem cell interaction and ECM-stem cell interaction, mimicking ECM is preferred as that can be precisely controlled by scaffold fabrication techniques, processing parameters or post-fabrication modifications. In order to mimic, it is essential to understand natural properties of ECM and their role in stem cell fate processes. Various studies involving different types of scaffolds that regulate stem cells fate by mimicking these ECM properties have been done.[2])

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What is a spinal cord injury?What are some signs and symptoms of spinal cord injury?How are spinal cord injuries diagnosed?How is SCI treated?What research is being done?How can I help with research?Where can I get more information?Appendix

A spinal cord injury (SCI) is damage to the tight bundle of cells and nerves that sends and receives signals from the brain to and from the rest of the body. The spinal cord extends from the lower part of the brain down through the lower back.

SCI can be caused by direct injury to the spinal cord itself or from damage to the tissue and bones (vertebrae) that surround the spinal cord. This damage can result in temporary or permanent changes in sensation, movement, strength, and body functions below the site of injury.

Injury and severity

The extent of disability depends on where along the spinal cord the injury occurs and the severity of the injury.

Loss of nerve function occurs below the level of injury. An injury higher on the spinal cord can cause paralysis in most of the body and affect all limbs (called tetraplegia or quadriplegia). A lower injury to the spinal cord may cause paralysis affecting the legs and lower body (called paraplegia).

A spinal cord injury can damage a few, many, or almost all of the nerve fibers that cross the site of injury. A variety of cells located in and around the injury site may also die. Some injuries having little or no nerve cell death may allow an almost complete recovery.

Type of injury

A spinal cord injury can be classified as complete or incomplete.

Primary damage is immediate and is caused directly by the injury. Secondary damage results from inflammation and swelling that can press on the spinal cord and vertebrae, as well as from changes in the activity of cells and cell death.

Common causes

Motor vehicle accidents and catastrophic falls are the most common causes of SCI in the United States. The rest are due to acts of violence (primarily gunshot wounds and assaults), sports injuries, medical or surgical injury, industrial accidents, diseases and conditions that can damage the spinal cord, and other less common causes.

For information on what makes up the spinal cord and spinal column, see the Appendix at the end of this document.

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A spinal cord injury can cause one or more symptoms including:

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How are spinal cord injuries diagnosed?

The emergency room physician will check for movement or sensation at or below the level of injury, as well as proper breathing, responsiveness, and weakness. Emergency medical tests for a spinal cord injury include:

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Immediate (acute) treatment

At the accident scene, emergency personnel will put a rigid collar around the neck and carefully place the person on a rigid backboard to prevent further damage to the spinal cord. Sometimes the person may be sedated to relax and prevent movement. A breathing tube may be inserted if the person has problems breathing and the body isnt receiving enough oxygen from the lungs.

Immediate treatment at the trauma center may include:

Possible Complications of SCI and treatment

Once someone has survived the injury and begins to cope psychologically and emotionally, the next concern is how to live with disabilities. Doctors are now able to predict with reasonable accuracy the likely long-term outcome of spinal cord injuries. This helps people experiencing SCI set achievable goals for themselves and gives families and loved ones a realistic set of expectations for the future.

Rehabilitation

Rehabilitation programs combine physical therapies with skill-building activities and counseling to provide social and emotional support, as well as to increase independence and quality of life.

A rehabilitation team is usually led by a doctor specializing in physical medicine and rehabilitation (called a physiatrist) and often includes social workers, physical and occupational therapists, recreational therapists, rehabilitation nurses, rehabilitation psychologists, vocational counselors, nutritionists, a case worker, and other specialists.

In the initial phase of rehabilitation, therapists emphasize regaining communication skills and leg and arm strength. For some individuals, mobility will only be possible with assistive devices such as a walker, leg braces, or a wheelchair. Communication skills such as writing, typing, and using the telephone may also require adaptive devices for some people with tetraplegia.

Adaptive devices also may help people with spinal cord injury to regain independence and improve mobility and quality of life. Such devices may include a wheelchair, electronic stimulators, assisted training with walking,neural prostheses (assistive devices that may stimulate the nerves to restore lost functions), computer adaptations, and other computer-assisted technology.

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Scientists continue to investigate new ways to better understand and treat spinal cord injuries.

Much of this research is conducted or funded by the National Institute of Neurological Disorders and Stroke (NINDS). NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world. Other NIH components, as well as the Department of Veterans Affairs, other Federal agencies, research institutions, and voluntary health organizations, also fund and conduct basic to clinical research related to improvement of function in paralyzed individuals.

The Brain Research through Advancing Innovative Technologies (BRAIN) Initiative brings together multiple federal agencies and private organizations to develop and apply new technologies to understand how complex circuits of nerve cells enable thinking, movement control, and perception. Research funded as part of the BRAIN Initiative that has the potential to improve the outlook for SCI includes:

Basic spinal cord function research studies how the normal spinal cord develops, processes sensory information, controls movement, and generates rhythmic patterns (like walking and breathing). Basic studies using cells and animal models provide an essential foundation for developing interventions for spinal cord injury.

Research on injury mechanisms focuses on what causes immediate harm and on the cascade of helpful and harmful bodily reactions that protect from or contribute to damage in the hours and days following a spinal cord injury. This includes testing of neuroprotective interventions in laboratory animals.

Current research on SCI is focused on advancing our understanding of four key principles of spinal cord repair:

Neural engineering strategies build on decades of pioneering NINDS investment that established the field of neural prostheses. For example, researchers are developing a networked functional electrical stimulation system to restore independence through combined implants for hand function, postural control, and bowel and bladder control. NINDS has also led development of experimental brain computer interfaces that enable people to control a computer cursor or robotic arm directly from their brains.

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Clinical research uses human volunteersboth those who are healthy or may have an illness or diseaseto help researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease. For information about finding and participating in clinical research visit NIH Clinical Research Trials and You at http://www.nih.gov/health/clinicaltrials. Use search terms such as spinal cord injury and tetraplegia to access current and completed trials involving spinal injury.

Other centers maintain registries of people interested in participating in ongoing or future clinical research studies. A multi-site network supported by the Christopher and Dana Reeve Foundation called the NeuroRecovery Network also accepts volunteer research participants. For more information, see http://www.christopherreeve.org/site/c.ddJFKRNoFiG/b.5399929/k.6F37/NeuroRecovery_Network.htm.

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For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute's Brain Resources and Information Network (BRAIN) at:

BRAINP.O. Box 5801Bethesda, MD 20824800-352-9424

Information also is available from the following organizations:

Christopher and Dana Reeve Foundation Email: Information@christopherreeve.org 973-379-2690 or 800-225-0292

Miami Project to Cure ParalysisEmail: miamiproject@miami.edu 305-243-6001 or 800-782-6387

National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) 202-401-4634; 202-245-7316 (TTY)

National Rehabilitation Information Center (NARIC) Landover, MD 20785301-459-5900; 800-346-2742; 301-459-5984 (TTY)

Paralyzed Veterans of America (PVA) Email: info@pva.orr 800-424-8200

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Anatomy of the spinal cord

The spinal cord is a soft, cylindrical column of tightly bundled nerve cells (neurons and glia), nerve fibers that transmit nerve signals (called axons), and blood vessels. It sends and receives information between the brain and the rest of the body. Millions of nerve cells situated in the spinal cord itself also coordinate complex patterns of movements such as rhythmic breathing and walking.

The spinal cord extends from the brain to the lower back through a canal in the center of the bones of the spine. Like the brain, the spinal cord is protected by three layers of tissue and is surrounded by the cerebrospinal fluid that acts as a cushion against shock or injury.

Inside the spinal cord is:

Other types of nerve cells sit just outside the spinal cord and relay information to the brain.

31 pairs of nerves, each of which contains thousands of axons, are divided into 4 regions having individual segments and link the spinal cord to muscles and other parts of the body:

The spinal column, which surrounds and protects the spinal cord, is made up of 33 rings of bone (called vertebrae), pads of semi-rigid cartilage (called discs), and narrow spaces called foramen that act as passages for spinal nerves to travel to and from the rest of the body. These are places where the spinal cord is particularly vulnerable to direct injury.

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"Spinal Cord Injury: Hope Through Research", NINDS, Publication date July 2013.

NIH Publication 13-NS-160

Back toSpinal Cord Injury Information Page

See a list of all NINDS Disorders

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Prepared by:Office of Communications and Public LiaisonNational Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesda, MD 20892

NINDS health-related material is provided for information purposes only and does not necessarily represent endorsement by or an official position of the National Institute of Neurological Disorders and Stroke or any other Federal agency. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient's medical history.

All NINDS-prepared information is in the public domain and may be freely copied. Credit to the NINDS or the NIH is appreciated.

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Spinal Cord Injury: Hope Through Research | National Institute of ...

Spinal Cord Stem Cells Comments Off on Spinal Cord Injury: Hope Through Research | National Institute of … | December 1st, 2022

Overview

Stem cells have the ability to divide for indefinite periods in culture and give rise to multiple specialized cell types. They can develop into blood, neurons, bone, muscle, skin and other cell types. They have emerged as a major tool for research into the causes of ALS, and in the search of new treatments.

Types of Stem Cells:

The field of stem cell research is progressing rapidly, and The ALS Association is spearheading work on several critical fronts. The research portfolio supports innovative projects using IPSCs for drug development and disease modeling. The Association is supporting an IPSC core at Cedars-Sinai Medical Center providing access to lines for researchers globally. Several of the big data initiatives are collecting skin cells or blood for IPSC generation, such asGenomic Translation for ALS Clinical Care (GTAC),Project MinE,NeuroLINCSandAnswer ALS. The ALS Association also sponsors pre-clinical studies and pilot clinical trials using stem cell transplant approaches to develop the necessary tools for stem cell transplant studies and to improve methods for safety and efficiency. We also support studies that involve isolating IPSCs to develop biomarkers for clinical trials throughALS ACT. In addition, the retigabine clinical trial that we sponsor uses iPSCs derived from participants in parallel with clinical data to help test whether the drug has the desired effect.

Stem cells are being used in many laboratories today for research into the causes of and treatments for ALS. Most commonly, researchers use iPSCs to make a unique source of motor neurons from individual ALS patients to try to understand why and how motor neurons die in ALS. Two types of motor neurons are affected in ALS are upper coriticospinal motor neurons, that when damaged, cause muscle spasticity (uncontrolled movement), and lower motor neurons, that when damaged, cause muscle weakness. Both types can be made from iPSCs to cover the range of pathology and symptoms found in ALS. Astrocytes, a type of support cell, called glia, of the central nervous system (CNS), are also being generated from iPSCs. It is well established that glia play a role in disease process and contribute to motor neuron death.

Motor neurons created from iPSCs have many uses. The availability of large numbers of identical neurons, made possible by iPSCs, has dramatically expanded the ability to search for new treatments. For example, they can also be used to screen for drugs that can alter the disease process. Motor neurons derived from iPSCs can be genetically modified to produce colored fluorescent markers that allow clear visualization under a microscope. The health of individual motor neurons can be tracked over time to understand if a test compound has a positive or negative effect.

Because iPSCs can be made from skin samples or blood of any person, researchers have begun to make cell lines derived from dozens of individuals with ALS. One advantage of iPSCs are that they capture a persons exact genetic material and provide an unlimited supply of cells that can be studied in a dish, which is like persons own avatar. Comparing the motor neurons derived from these cells lines allows them to ask what is common, and what is unique, about each case of ALS, leading to further understanding of the disease process. They are also used to correlate patients clinical parameters, such as site of onset and severity with any changes in the same patients motor neurons.

Stem cells may also have a role to play in treating the disease. The most likely application may be to use stem cells or cells derived from them to deliver growth factors or protective molecules to motor neurons in the spinal cord. Clinical trials of such stem cell transplants are in the early stages, but appear to be safe. In addition, transplantation of healthy astrocytes have the potential to be beneficial in supporting motor neurons in the brain and spinal cord.

While the idea of replacing dying motor neurons with new ones derived from stem cells is appealing, using stem cells as a delivery tool to provide trophic factors to motor neurons is a more realistic and feasible approach. The significant challenge to replacing dying motor neurons is making the appropriate connections between muscles and surrounding neurons.

Isolation of IPSCs from people with ALS in clinical trials is extremely valuable for the identification of unique signatures in the presence or absence of a specific treatment approach and as a read out to test whether a drug or test compound has an impact on the health of motor neurons and/or astrocytes. A positive result gives researchers confidence to move forward to more advanced clinical trials. For example, The ALS Association is currently funding a clinical trial to test the effects of retigabine on motor neurons, which use the enrolled patients individual iPSCs lines derived from collected skin samples and testing whether there is a change in the excitability of motor neurons in people with ALS. (see above).

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Stem Cells | The ALS Association

Skin Stem Cells Comments Off on Stem Cells | The ALS Association | November 22nd, 2022

Stem Cell Therapy

Cell therapy involves the direct administration of cells into the body for healing purposes. The units of therapy in this approach are single cells. For regenerative medicine, the ultimate objective of cell therapy is to establish a long-term graft with the capacity to perform organ functions. A practical example is bone marrow transplantation, in which HSC are the units of therapy, engraft in the bone marrow, and repopulate the entire blood lineage.105

Intravenous administration describes the direct injection of dissociated cells into the bloodstream using a syringe. It is the simplest delivery route for cell therapies and is used for HSC therapy in the clinic. Kidney cells, however, are different from blood cells and do not typically circulate throughout the body. The kidney is furthermore a densely-packed organ with no obvious route for stem cells to traverse from the bloodstream into the nephrons. Whether kidney stem cells have the ability to engraft and regenerate the kidney after intravenous administration therefore needs to be tested in preclinical animal models. In these experiments, the kidneys are typically subjected to acute injury. This damages the glomerular filtration barrier, which can enhance penetration of cells into the kidney and subsequent engraftment.

In one example, human iPS cell-derived cells expressing a variety of NPC and adult kidney cell markers were injected into the mouse tail vein 24 hours after administration of the nephrotoxic drug cisplatin.106 Extensive engraftment was reported in proximal tubules, which coincided with a 55% reduction in urea levels in treated mice, compared with control animals administered with saline or undifferentiated iPS cells.106 These experiments suggest a possible benefit of iPS-derived kidney cells on kidney injury. However, the isolated cells were not shown to demonstrate the ability to form kidney organoids with segmented nephrons. It is therefore unclear whether the implanted cells contained bona fide NPC or whether new nephrons were actually formed.

Intravenous administration has also been applied to adult kidney cell populations. Human glomerular epithelial transitional cells (see earlier), administered intravenously into a mouse model of chemically-induced podocytopathy, were found in glomeruli, and were associated with a decrease in proteinuria.107 These cells also contributed to tubules after acute injury.80 As these cells cannot form new nephrons, this approach seeks to repair and replace, rather than to completely regenerate.

MSC can be readily obtained, for instance from a patient's adipose tissue. Intravenous administration of MSC in experimental models can have a beneficial effect on ischemia-reperfusion injury.99,102,108 This benefit can be obtained even in the absence of MSC engraftment, likely via a paracrine effect. However, MSC administered to injured kidneys do not contribute tangibly to new nephron formation and can differentiate ectopically into undesirable fat cells or fibroblasts within glomeruli.108,109 Collectively, these findings suggest that intravenous administration of cell therapeutics may provide some benefit in cases where the glomerular filtration barrier has been compromised but may also have unwanted side effects.

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Cell Therapy - an overview | ScienceDirect Topics

IPS Cell Therapy Comments Off on Cell Therapy – an overview | ScienceDirect Topics | November 22nd, 2022