Stem cell treatments

Stem cell treatments are a type of intervention strategy that introduces new cells into damaged tissue in order to treat disease or injury. Many medical researchers believe that stem cell treatments have the potential to change the face of human disease and alleviate suffering.[1] The ability of stem cells to self-renew and give rise to subsequent generations with variable degrees of differentiation capacities,[2] offers significant potential for generation of tissues that can potentially replace diseased and damaged areas in the body, with minimal risk of rejection and side effects.

See also: Cell therapy

A number of stem cell therapies exist, but most are at experimental stages or costly, with the notable exception of bone marrow transplantation. Medical researchers anticipate that adult and embryonic stem cells will soon be able to treat cancer, Type 1 diabetes mellitus, Parkinson's disease, Huntington's disease, Celiac Disease, cardiac failure, muscle damage and neurological disorders, and many others.[3] Nevertheless, before stem cell therapeutics can be applied in the clinical setting, more research is necessary to understand stem cell behavior upon transplantation as well as the mechanisms of stem cell interaction with the diseased/injured microenvironment.[3]

Contents

Current treatments

Further information: Hematopoietic stem cell transplantation

For over 30 years, bone marrow, and more recently, umbilical cord blood stem cells, have been used to treat cancer patients with conditions such as leukemia and lymphoma.[4] During chemotherapy, most growing cells are killed by the cytotoxic agents. These agents, however, cannot discriminate between the leukemia or neoplastic cells, and the hematopoietic stem cells within the bone marrow. It is this side effect of conventional chemotherapy strategies that the stem cell transplant attempts to reverse; a donor's healthy bone marrow reintroduces functional stem cells to replace the cells lost in the host's body during treatment.

Potential treatments

Brain damage

Stroke and traumatic brain injury lead to cell death, characterized by a loss of neurons and oligodendrocytes within the brain. Healthy adult brains contain neural stem cells which divide to maintain general stem cell numbers, or become progenitor cells. In healthy adult animals, progenitor cells migrate within the brain and function primarily to maintain neuron populations for olfaction (the sense of smell). Interestingly, in pregnancy and after injury, this system appears to be regulated by growth factors and can increase the rate at which new brain matter is formed. Although the reparative process appears to initiate following trauma to the brain, substantial recovery is rarely observed in adults, suggesting a lack of robustness.

Stem cells may also be used to treat brain degeneration, such as in Parkinson's and Alzheimer's disease.[5][6]

Cancer

The development of gene therapy strategies for treatment of intra-cranial tumours offers much promise, and has shown to be successful in the treatment of some dogs;[7] although research in this area is still at an early stage. Using conventional techniques, brain cancer is difficult to treat because it spreads so rapidly. Researchers at the Harvard Medical School transplanted human neural stem cells into the brain of rodents that received intracranial tumours. Within days, the cells migrated into the cancerous area and produced cytosine deaminase, an enzyme that converts a non-toxic pro-drug into a chemotheraputic agent. As a result, the injected substance was able to reduce the tumor mass by 81 percent. The stem cells neither differentiated nor turned tumorigenic.[8] Some researchers believe that the key to finding a cure for cancer is to inhibit proliferation of cancer stem cells. Accordingly, current cancer treatments are designed to kill cancer cells. However, conventional chemotherapy treatments cannot discriminate between cancerous cells and others. Stem cell therapies may serve as potential treatments for cancer.[9] Research on treating Lymphoma using adult stem cells is underway and has had human trials. Essentially, chemotherapy is used to completely destroy the patients own lymphocytes, and stem cells injected, eventually replacing the immune system of the patient with that of the healthy donor.

Spinal cord injury

A team of Korean researchers reported on November 25, 2003, that they had transplanted multipotent adult stem cells from umbilical cord blood to a patient suffering from a spinal cord injury and that following the procedure, she could walk on her own, without difficulty. The patient had not been able to stand up for roughly 19 years. For the unprecedented clinical test, the scientists isolated adult stem cells from umbilical cord blood and then injected them into the damaged part of the spinal cord.[10][11]

According to the October 7, 2005 issue of The Week, University of California, Irvine researchers transplanted multipotent human fetal-derived neural stem cells into paralyzed mice, resulting in locomotor improvements four months later. The observed recovery was associated with differentiation of transplanted cells into new neurons and oligodendrocytes- the latter of which forms the myelin sheath around axons of the central nervous system, thus insulating neural impulses and facilitating communication with the brain.[12]

In January 2005, researchers at the University of Wisconsin–Madison differentiated human blastocyst stem cells into neural stem cells, then into pre-mature motor neurons, and finally into spinal motor neurons, the cell type that, in the human body, transmits messages from the brain to the spinal cord and subsequently mediates motor function in the periphery. The newly generated motor neurons exhibited electrical activity, the signature action of neurons. Lead researcher Su-Chun Zhang described the process as "[teaching] the blastocyst stem cells to change step by step, where each step has different conditions and a strict window of time."

Transformation of blastocyst stem cells into motor neurons had eluded researchers for decades. While Zhang's findings were a significant contribution to the field, the ability of transplanted neural cells to establish communication with neighboring cells remains unclear. Accordingly, studies using chicken embryos as a model organism can be an effective proof-of-concept experiment. If functional, the new cells could be used to treat diseases like Lou Gehrig's disease, muscular dystrophy, and spinal cord injuries.

Heart damage

Several clinical trials targeting heart disease have shown that adult stem cell therapy is safe, effective, and equally efficient in treating old and recent infarcts.[13] Adult stem cell therapy for treating heart disease was commercially available in at least five continents at the last count (2007).

Possible mechanisms of recovery include:[5]

It may be possible to have adult bone marrow cells differentiate into heart muscle cells.[5]

Haematopoiesis (blood cell formation)

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

Fully mature human red blood cells may be generated ex vivo by hematopoietic stem cells (HSCs), which are precursors of red blood cells. In this process, HSCs are grown together with stromal cells, creating an environment that mimics the conditions of bone marrow, the natural site of red blood cell growth. Erythropoietin, a growth factor, is added, coaxing the stem cells to complete terminal differentiation into red blood cells.[14] Further research into this technique should have potential benefits to gene therapy, blood transfusion, and topical medicine.

Baldness

Hair follicles also contain stem cells, and some researchers predict research on these follicle stem cells may lead to successes in treating baldness through an activation of the stem cells progenitor cells. This treatment is expected to work by activating already existing stem cells on the scalp. Later treatments may be able to simply signal follicle stem cells to give off chemical signals to nearby follicle cells which have shrunk during the aging process, which in turn respond to these signals by regenerating and once again making healthy hair. Most recently, Dr. Aeron Potter of the University of California has claimed that stem cell therapy led to a significant and visible improvement in follicular hair growth . Results from his experiments are under review by the journal Science (journal).

Missing teeth

In 2004, scientists at King's College London discovered a way to cultivate a complete tooth in mice[15] and were able to grow them stand-alone in the laboratory. Researchers are confident that this technology can be used to grow live teeth in human patients.

In theory, stem cells taken from the patient could be coaxed in the lab into turning into a tooth bud which, when implanted in the gums, will give rise to a new tooth, and would be expected to grow within two months.[16] It will fuse with the jawbone and release chemicals that encourage nerves and blood vessels to connect with it. The process is similar to what happens when humans grow their original adult teeth.

Many challenges remain, however, before stem cells could be a choice for the replacement of missing teeth in the future.[17]

Deafness

Heller has reported success in re-growing cochlea hair cells with the use of embryonic stem cells.[18]

Blindness and vision impairment

Since 2003, researchers have successfully transplanted corneal stem cells into damaged eyes to restore vision. "Sheets of retinal cells used by the team are harvested from aborted fetuses, which some people find objectionable." When these sheets are transplanted over the damaged cornea, the stem cells stimulate renewed repair, eventually restore vision.[19] The latest such development was in June 2005, when researchers at the Queen Victoria Hospital of Sussex, England were able to restore the sight of forty patients using the same technique. The group, led by Dr. Sheraz Daya, was able to successfully use adult stem cells obtained from the patient, a relative, or even a cadaver. Further rounds of trials are ongoing.[20]

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

The University Hospital of New Jersey reports that the success rate for growth of new cells from transplanted stem cells varies from 25 percent to 70 percent.[21]

In 2009, researchers at the University of Pittsburgh Medical center demonstrated that stem cells collected from human corneas can restore transparency without provoking a rejection response in mice with corneal damage.[22]

Amyotrophic lateral sclerosis

Stem cells have resulted in significant locomotor improvements in rats with an Amyotrophic lateral sclerosis-like disease. In a rodent model that closely mimics the human form of ALS, animals were injected with a virus to kill the spinal cord motor nerves which mediate movement. Animals subsequently received stem cells in the spinal cord. Transplanted cells migrated to the sites of injury, contributed to regeneration of the ablated nerve cells, and restored locomotor function.[23]

Graft vs. host disease and Crohn's disease

Phase III clinical trials expected to end in second-quarter 2008 were conducted by Osiris Therapeutics using their in-development product Prochymal, derived from adult bone marrow. The target disorders of this therapeutic are graft-versus-host disease and Crohn's disease.[24]

Neural and behavioral birth defects

A team of researchers led by Prof. Joseph Yanai were able to reverse learning deficits in the offspring of pregnant mice who were exposed to heroin and the pesticide organophosphate.[25][26] This was done by direct neural stem cell transplantation into the brains of the offspring. The recovery was almost 100 percent, as shown both in behavioral tests and objective brain chemistry tests. Behavioral tests and learning scores of the treated mice showed rapid improvement after treatment, providing results that rivaled non-treated mice. On the molecular level, brain chemistry of the treated animals was also restored to normal. Through the work, which was supported by the US National Institutes of Health, the US-Israel Binational Science Foundation and the Israel anti-drug authorities, the researchers discovered that the stem cells worked even in cases where most of the cells died out in the host brain.

The scientists found that before they die the neural stem cells succeed in inducing the host brain to produce large numbers of stem cells which repair the damage. These findings, which answered a major question in the stem cell research community, were published in January 2008 in the leading journal, Molecular Psychiatry. Scientists are now developing procedures to administer the neural stem cells in the least invasive way possible - probably via blood vessels, making therapy practical and clinically feasible. Researchers also plan to work on developing methods to take cells from the patient's own body, turn them into stem cells, and then transplant them back into the patient's blood via the blood stream. Aside from decreasing the chances of immunological rejection, the approach will also eliminate the controversial ethical issues involved in the use of stem cells from human embryos.[27]

Diabetes

Diabetes patients lose the function of insulin-producing beta cells within the pancreas. Human embryonic stem cells may be grown in cell culture and stimulated to form insulin-producing cells that can be transplanted into the patient.

However, clinical success is highly dependent on the development of the following procedures:[5]

Orthopaedics

Clinical case reports in the treatment of orthopaedic conditions have been reported. To date, the focus in the literature for musculoskeletal care appears to be on mesenchymal stem cells. Centeno et al. have published MRI evidence of increased cartilage and meniscus volume in individual human subjects.[28][29] The results of trials that include a large number of subjects, are yet to be published. However, a published safety study conducted in a group of 227 patients over a 3-4 year period shows adequate safety and minimal complications associated with mesenchymal cell transplantation.[30]

Wakitani has also published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.[31]

Wound healing

Stem cells can also be used to stimulate the growth of human tissues. In an adult, wounded tissue is most often replaced by scar tissue, which is characterized in the skin by disorganized collagen structure, loss of hair follicles and irregular vascular structure. In the case of wounded fetal tissue, however, wounded tissue is replaced with normal tissue through the activity of stem cells.[32] A possible method for tissue regeneration in adults is to place adult stem cell "seeds" inside a tissue bed "soil" in a wound bed and allow the stem cells to stimulate differentiation in the tissue bed cells. This method elicits a regenerative response more similar to fetal wound-healing than adult scar tissue formation.[32] Researchers are still investigating different aspects of the "soil" tissue that are conducive to regeneration.[32]

Infertility

Culture of human embryonic stem cells in mitotically inactivated porcine ovarian fibroblasts (POF) causes differentiation into germ cells (precursor cells of oocytes and spermatozoa), as evidenced by gene expression analysis.[33]

Human embryonic stem cells have been stimulated to form Spermatozoon-like cells, yet still slightly damaged or malformed.[34] It could potentially treat azoospermia.

Clinical Trials

On January 23, 2009, the US Food and Drug Administration gave clearance to Geron Corporation for the initiation of the first clinical trial of an embryonic stem cell-based therapy on humans. The trial will evaluate the drug GRNOPC1, embryonic stem cell-derived oligodendrocyte progenitor cells, on patients with acute spinal cord injury.

As of mid 2010 hundreds of phase III clinical trials involving stem cells have been registered.[35]

Stem cell use in animals

Veterinary applications

Potential contributions to veterinary medicine

Research currently conducted on horses, dogs, and cats can benefit the development of stem-cell treatments in veterinary medicine and can target a wide range of injuries and diseases such as myocardial infarction, stroke, tendon and ligament damage, osteoarthritis, osteochondrosis and muscular dystrophy both in large animals, as well as humans.[36][37][38][39] While investigation of cell-based therapeutics generally reflects human medical needs, the high degree of frequency and severity of certain injuries in racehorses has put veterinary medicine at the forefront of this novel regenerative approach.[40] Companion animals can serve as clinically relevant models that closely mimic human disease.[41][42]

Development of regenerative treatment models

Veterinary applications of stem cell therapy as a means of tissue regeneration have been largely shaped by research that began with the use of adult-derived mesenchymal stem cells to treat animals with injuries or defects affecting bone, cartilage, ligaments and/or tendons.[43][44][45] Because mesenchymal stem cells can differentiate into the cells that make up bone, cartilage, tendons, and ligaments (as well as muscle, fat, and possibly other tissues), they have been the main type of stem cells studied in the treatment of diseases affecting these tissues.[44][46] Mesenchymal stem cells are primarily derived from adipose tissue or bone marrow. Since an elevated immune response following cell transplantation may result in rejection of exogenous cells (except in the case of cells derived from a very closely genetically related individual), mesenchymal stem cells are often derived from the patient prior to injection in a process known as autologous transplantation.[47] Surgical repair of bone fractures in dogs and sheep has demonstrated that engraftment of mesenchymal stem cells derived from a genetically different donor within the same species, termed allogeneic transplantation, does not elicit an immunological response in the recipient animal and can mediate regeneration of bone tissue in major bony fractures and defects.[48][49] Stem cells can speed up bone repair in fractures/defects that would normally require extensive grafting, suggesting that mesenchymal stem cell use may provide a useful alternative to conventional grafting techniques.[48][49] Treating tendon and ligament injuries in horses using stem cells, whether derived from adipose tissue or bone-marrow, has support in the veterinary literature.[50][51] While further studies are necessary to fully characterize the use of cell-based therapeutics for treatment of bone fractures, stem cells are thought to mediate repair via five primary mechanisms: 1) providing an antiinflammatory effect, 2) homing to damaged tissues and recruiting other cells, such as endothelial progenitor cells, that are necessary for tissue growth, 3) supporting tissue remodeling over scar formation, 4) inhibiting apoptosis, and 5) differentiating into bone, cartilage, tendon, and ligament tissue.[51][52]
Significance of stem cell microenvironments
The microenvironment into which stem cells are transplanted significantly alters the capacity of engrafted cells for recovery and repair. The microenviroment provides growth factors and other chemical signals that guide appropriate differentiation of transplanted cell populations and direct transplanted cells to sites of trauma or disease. Repair and recovery can then be mediated via three primary mechanisms: 1) formation and/or recruitment of new blood cells to the damaged region; 2) prevention of programed cell death or apoptosis; and 3) suppression of inflammation.[3][47][49] To further enrich blood supply to the damaged areas, and consequently promote tissue regeneration, platelet-rich plasma could be used in conjunction with stem cell transplantation.[47][53] The efficacy of some stem cell populations may also be affected by the method of delivery; for instance, to regenerate bone, stem cells are often introduced in a scaffold where they produce the minerals necessary for generation of functional bone.[3][47][49][53]
Sources of autologous (patient-derived) stem cells
Autologous stem cells intended for regenerative therapy are generally isolated either from the patient's bone marrow or from adipose tissue. The number of stem cells transplanted into damaged tissue may alter efficacy of treatment. Accordingly, stem cells derived from bone marrow aspirates, for instance, are cultured in specialized laboratories for expansion to millions of cells.[49][53] Although adipose-derived tissue also requires processing prior to use, the culturing methodology for adipose-derived stem cells is not as extensive as that for bone marrow-derived cells.[54][55] While it is thought that bone-marrow derived stem cells are preferred for bone, cartilage, ligament, and tendon repair, others believe that the less challenging collection techniques and the multi-cellular microenvironment already present in adipose-derived stem cell fractions make the latter the preferred source for autologous transplantation.[47]

Currently available treatments for horses and dogs suffering from orthopaedic conditions

Autologous or allogeneic stem cells are currently used as an adjunctive therapy in the surgical repair of some types of fractures in dogs and horses.[49][56] Autologous stem cell-based treatments for ligament injury, tendon injury, osteoarthritis, osteochondrosis, and sub-chondral bone cysts have been commercially available to practicing veterinarians to treat horses since 2003 in the United States and since 2006 in the United Kingdom. Autologous stem-cell based treatments for tendon injury, ligament injury, and osteoarthritis in dogs have been available to veterinarians in the United States since 2005. Over 3000 privately-owned horses and dogs have been treated with autologous adipose-derived stem cells. The efficacy of these treatments has been shown in double-blind clinical trials for dogs with osteoarthritis of the hip and elbow and horses with tendon damage.[57][58] The efficacy of using stem cells, whether adipose-derived or bone-marrow derived, for treating tendon and ligament injuries in horses has support in the veterinary literature.[50][51]

Developments in Stem Cell Treatments in Veterinary Internal Medicine

Currently, research is being conducted to develop stem cell treatments for: 1) horses suffering from COPD, neurologic disease, and laminitis; and 2) dogs and cats suffering from heart disease, liver disease, kidney disease, neurologic disease, and immune-mediated disorder

Embryonic stem cell controversy

Main article: Stem cell controversy

There is widespread controversy over the use of human embryonic stem cells. This controversy primarily targets the techniques used to derive new embryonic stem cell lines, which often requires the destruction of the blastocyst. Opposition to the use of human embryonic stem cells in research is often based on philosophical, moral or religious objections.[59]

Stem cell treatments around the world

China

Stem cell research and treatment is currently being practiced at a clinical level in the People's Republic of China. The Ministry of Health of the People's Republic of China has permitted the use of stem cell therapy for conditions beyond those approved of in Western countries such as the United States, United Kingdom, and Australia. The Western World has scrutinized China for its failed attempts to meet international documentation standards of these trials and procedures, despite the overwhelmingly positive anecdotal results.[60]

Stem cell therapies provided in China utilize a variety of cell types including umbilical cord stem cells and olfactory ensheathing cells. The stem cells are then expanded in centralized blood banks before being used in stem cell treatments. State-funded companies based in the Shenzhen Hi-Tech Industrial Zone treat the symptoms of numerous disorders with adult stem cell therapy. Hospitals throughout eastern China provide numerous therapies to patients in coordination with the stem cell providers. These companies' therapies are currently focused on the treatment of neurodegenerative and cardiovascular disorders. The most radical successes of Chinese adult stem cell therapy have been in treating the brain. These therapies administer stem cells directly to the brain to promote greater motor and brain function in patients with Cerebral Palsy, Alzheimer's, and brain injuries. However, retrospective studies have shown that Chinese use of fetal-derived brain tissue in spinal cord injured human subjects were not as promising as once thought: the phenotype and the fate of the transplanted cells, described as olfactory ensheathing cells, were unknown. As well, perioperative morbidity and lack of functional benefit were identified as the most serious clinical shortcomings.[60] Furthermore, the extent of regulatory policy in the use of stem cell therapies in China is unclear.[61] In the absence of a valid clinical trials protocol, and more regulatory oversight, Western regulatory agencies advise patients and physicians to be cautious when selecting Chinese stem cell therapeutic centers.[60]

Mexico

Stem cell treatment is currently being practiced at a clinical level in Mexico. An International Health Department Permit (COFEPRIS) is required. This permit allows the use of stem cell types beyond those approved of in Western countries such as the United States or Europe. Stem cell therapies provided in Mexico utilize patient Adipose, Bone Marrow, or Donor Placenta sources.

South Korea

In 2005, South Korean scientists claimed to have generated stem cells that were tailored to match the recipient. Each of the 11 new stem cell lines was developed using somatic cell nuclear transfer (SCNT) technology. The resultant cells were thought to match the genetic material of the recipient, thus suggesting minimal to no cell rejection.[62]

This study, however, was eventually discredited as the primary researcher,Dr. Woo Suk Hwang, admitted to using cells obtained from his research staff. In Dec 2005, claims were put forward that his research had been manipulated to wrongfully indicate positive results. Later that month, these claims were confirmed by an academic panel.[63]

Ukraine

Today, Ukraine is permitted to perform clinical trials of stem cell treatments (Order of the MH of Ukraine № 630 "About carrying out clinical trials of stem cells", 2008) for the treatment of these pathologies: pancreatic necrosis, cirrhosis, hepatitis, burn disease, diabetes, multiple sclerosis, critical lower limb ischemia. The first medical institution granted the right to conduct clinical trials became the "Institute of Cell Therapy"(Kiev).

See also

External links

References

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