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Stem cell treatments are a type of genetic medicine that introduce new cells into damaged tissue in order to treat a disease or injury. Many medical researchers believe that stem cell treatments have the potential to change the face of human disease and alleviate suffering. The ability of stem cells to self-renew and give rise to subsequent generations that can differentiate ^[1] offers a large potential to culture tissues that can replace diseased and damaged tissues in the body, without the risk of rejection and side effects.

A number of stem cell treatments exist, although most are still experimental and/or costly, with the notable exception of bone marrow transplantation. Medical researchers anticipate one day being able to use technologies derived from adult and embryonic stem cell research to treat cancer, Type 1 diabetes mellitus, Parkinson's disease, Huntington's disease, cardiac failure, muscle damage and neurological disorders, along with many others.^[2]

More research is needed concerning both stem cell behavior and the mechanisms of the diseases they could be used to treat before most of these experimental treatments become realities.^[2]

Contents 1 Current treatments 2 Potential treatments 2.1 Brain damage 2.2 Cancer 2.3 Spinal cord injury 2.4 Heart damage 2.5 Haematopoiesis (blood cell formation) 2.6 Baldness 2.7 Missing teeth 2.8 Deafness 2.9 Blindness and vision impairment 2.10 Amyotrophic lateral sclerosis 2.11 Graft vs. host disease and Crohn's disease 2.12 Neural and behavioral birth defects 2.13 Diabetes 2.14 Orthopedics 2.15 Wound healing 2.16 Infertility 3 Clinical Trials 4 Stem cell use in animals 4.1 Veterinary applications 4.1.1 Veterinary research can contribute to human medicine 4.1.2 Veterinary research has developed regenerative treatment models, particularly involving mesenchymal stem cells 4.1.2.1 The significance of stem cell microenvironments 4.1.2.2 Sources of autologous (patient-derived) mesenchymal stem cells 4.1.3 Currently Available Treatments for Horses and Dogs Suffering from Orthopedic Conditions 4.1.4 Developments in Stem Cell Treatments in Veterinary Internal Medicine 4.2 Rats 5 Controversy 6 Stem cell treatments around the world 6.1 China 6.2 India 7 External links 8 References

[edit] Current treatments

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. During chemotherapy, most growing cells are killed by the cytotoxic agents. These agents not only kill the leukemia or neoplastic cells, but also the haematopoietic stem cells within the bone marrow. It is this side effect of the chemotherapy that the stem cell transplant attempts to reverse; the donor's healthy bone marrow reintroduces functional stem cells to replace those lost in the treatment.

[edit] Potential treatments

[edit] 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, these divide and act 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. In the case of brain injury, although the reparative process appears to initiate, 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.^[3]

[edit] Cancer

Research injecting neural (adult) stem cells into the brains of dogs has shown to be very successful in treating cancerous tumors. With traditional techniques brain cancer is almost impossible to treat because it spreads so rapidly. Researchers at the Harvard Medical School induced intracranial tumours in rodents. Then, they injected human neural stem cells. Within days the cells had 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 tumor mass by 81 percent. The stem cells neither differentiated nor turned tumorigenic.^[4] Some researchers believe that the key to finding a cure for cancer is to inhibit cancer stem cells, where the cancer tumor originates. Currently, cancer treatments are designed to kill all cancer cells, but through this method, researchers would be able to develop drugs to specifically target these stem cells.^[5]

[edit] Spinal cord injury

A team of Korean researchers reported on November 25, 2004, that they had transplanted multipotent adult stem cells from an umbilical cord blood to a patient suffering from a spinal cord injury and that she can now walk on her own, without difficulty. The patient had not been able 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.^{[6] [7]}

According to the October 7, 2005 issue of The Week, University of California researchers injected human embryonic stem cells into paralyzed mice, which resulted in the mice regaining the ability to move and walk four months later. The researchers discovered upon dissecting the mice that the stem cells regenerated not only the neurons, but also the cells of the myelin sheath, a layer of cells which insulates neural impulses and speeds them up, facilitating communication with the brain (damage to which is often the cause of neurological injury in humans).

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

Transforming blastocyst stem cells into motor neurons had eluded researchers for decades. The next step will be to test if the newly generated neurons can communicate with other cells when transplanted into a living animal; the first test will be in chicken embryos. Su-Chun said their trial-and-error study helped them learn how motor neuron cells, which are key to the nervous system, develop in the first place. The new cells could be used to treat diseases like Lou Gehrig's disease, muscular dystrophy, and spinal cord injuries.^{[citation needed]}

[edit] Heart damage

Several clinical trials targeting heart disease have shown that adult stem cell therapy is safe and effective, and is equally efficient in old as well as recent infarcts. ^[8] Adult stem cell therapy for heart disease was commercially available on at least five continents at the last count (2007).

Possible mechanisms are:^[3]

• Generation of heart muscle cells
• Stimulation of growth of new blood vessels that repopulate the heart tissue
• Secretion of growth factors, rather than actually incorporating into the heart
• Assistance via some other mechanism

It may be possible to have adult bone marrow cells differentiate into heart muscle cells.^[3]

[edit] 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, this system is a hot spot for degradation upon the pathogenesis of disease, and because of the critical role that it plays in organismal defense, its degradation is often fatal to the system as a whole. Diseases of hematopoietic cells are called hematopathology. The specificity of the immune cells is what allows them to recognize foreign antigens, causing further challenges in the treatment of immune disease. Identical matches between donor and recipient must be made for successful transplantation treatments, while matches are uncommon, even between first-degree relatives. Research using both hematopoietic adult stem cells and embryonic stem cells has contributed great insight into 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.^[9] Further research into this technique should have potential benefits to gene therapy, blood transfusion, and topical medicine.

[edit] 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 "hair multiplication", also known as "hair cloning". This treatment is expected to work through taking stem cells from existing follicles, multiplying them in cultures, and implanting the new follicles into 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. ^[10]

[edit] Missing teeth

In 2004, scientists at King's College London discovered a way to cultivate a complete tooth in mice^[11] 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, which would be expected to take two months to grow.^[12] 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.^[13]

[edit] Deafness

There has been success in re-growing cochlea hair cells with the use of stem cells.^[14]

[edit] Blindness and vision impairment

Since 2003, researchers have successfully transplanted retinal stem cells into damaged eyes to restore vision. Using embryonic stem cells, scientists are able to grow a thin sheet of totipotent stem cells in the laboratory. When these sheets are transplanted over the damaged retina, the stem cells stimulate renewed repair, eventually restoring vision.^[15] 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.^[16]

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 an 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 cornea has the remarkable property that it does not contain any blood vessels, making it relatively easy to transplant. The majority of corneal transplants carried out today are due to a degenerative disease called keratoconus.

The University Hospital of New Jersey claims a success rate growing the new cells from transplanted stem cells varies from 25 percent to 70 percent.^[17]

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.^[18]

[edit] Amyotrophic lateral sclerosis

Stem cells have cured rats with an Amyotrophic lateral sclerosis-like disease. The rats were injected with a virus to kill the spinal cord motor nerves related to leg movement, succeeded by injections of stem cells into their spinal cords. These migrated (passed through many layers of tissues) to the sites of injury where they were able to regenerate the dead nerve cells restoring the rats which were once again able to walk.^[19]

[edit] 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.^[20]

[edit] 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. This was done by direct neural stem cell transplantation into the brains of the offspring. The recovery was almost 100 percent, as proved in behavioral tests in which the treated animals improved to normal behavior and learning scores after the transplantation. 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 earlier this year 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.^[21]

[edit] Diabetes

Diabetes patients lose the function of their insulin-producing beta cells of their 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, success depends on developing procedures in all required steps:^[3]

• Have the cells proliferate and generate sufficient amount of tissue
• Differentiation into the right cell type
• Survival of the cells in the recipient (prevention of transplant rejection)
• Integration with the surrounding tissue in the body
• Function appropriately in long-term

[edit] Orthopedics

Clinical case reports in the treatment of orthopedic 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, though it is unclear how the MRI results compare to clinical response.^{[22] [23]} However, each of these articles only describes one lucky individual and the results of trials including more patients are yet to be published making it hard to extrapolate the efficacy and safety. It has also yet to be shown that these results apply to a larger group of patients.

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.^[24]

[edit] Wound healing

In one experimental method in regenerative medicine, stem cells are 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.^[25] 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.^[25] Researchers are still investigating different aspects of the "soil" tissue that are conducive to regeneration.^[25]

[edit] Infertility

Human embryonic stem cells have been stimulated to form Spermatozoon-like cells, yet still slightly damaged or malformed. ^[26] It could potentially treat azoospermia.

[edit] Clinical Trials

Stem Cell therapy has been researched in various clinical trials for a variety of treatments.

The U.S. National Institutes of Health performs a variety of stem cell clinical trials to the public and post these at their website: http://www.clinicaltrials.gov/ct2/results?term=stem+cell. This website allows those interested in alternative treatments to check the availabilities and locations of clinical trials being performed all over the country.

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

[edit] Stem cell use in animals

[edit] Veterinary applications

[edit] Veterinary research can contribute to human medicine

Research currently conducted on horses, dogs, and cats can benefit the development of stem-cell treatments in veterinary medicine, but may also contribute to developing those in human medicine for a range injuries and diseases such as myocardial infarction, stroke, tendon and ligament damage, osteoarthritis, osteochondrosis and muscular dystrophy.^{[27][28][29][30]} Research into using stem cells for therapeutic purposes generally reflects human medical needs, but the high degree of frequency and severity of certain injuries in racehorses has put veterinary medicine at the forefront of this novel regenerative approach.^[31] Companion animals may be superior models than typical mouse models for human disease. ^[32][33]

[edit] Veterinary research has developed regenerative treatment models, particularly involving mesenchymal stem cells

Veterinary applications of stem cell therapy as a means of regenerating new tissue as an alternative to scar (less functional tissue) formation have developed from research that has been conducted since 1998 using adult-derived mesenchymal stem cells to treat animals with injuries or defects affecting bone, cartilage, ligaments and/or tendons.^[34][35][36] 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.^[37][38] The two main sources of mesenchymal stem cells used are adipose tissue or bone marrow. Because an animal's immune system mounts a detrimental response to transplanted cells in general, except in the case of cells from a very closely genetically related individual, therapeutic stem cells are most often derived from the patient prior to therapy.^[39] These are termed autologous stem cells. In surgical repair of bone fractures in dogs and sheep, veterinarians have found that grafting mesenchymal stem cells from a genetically different donor of the same species, termed allogeneic mesenchymal stem cells, does not elicit an immunological response in the patient and can be used to help regenerate bone tissue in major bony fractures and defects.^[40][41] Stem cells can help speed the repair of bone fractures and defects that would normally require extensive grafting and mesenchymal stem cell use in surgical implants may actually be superior to traditional grafting techniques.^[40][41] Treating tendon and ligament injuries in horses using stem cells, whether derived from adipose tissue or bone-marrow, has support in the veterinary literature.^[42][43] Although more specific characterization and localization studies of the stem-cell containing fractions used in regenerative medicine have been identified as necessary in the veterinary literature, there is scientific evidence supporting that stem cells can improve healing by five main means: 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.^[44][45]

[edit] The significance of stem cell microenvironments

To regenerate bone, stem cells must be in a carrier system that provides the appropriate context: a scaffold, upon which the introduced stem cells develop, the minerals needed to develop properly into functional bone, and growth factors that signal to the mesenchymal stem cell to differentiate into bone cells.^{[39][41][46][47]} Whether the stem cells are to heal bone or any other type of tissue, the context or microenvironment in which a group of introduced stem cells is placed is essential for effective healing, not only to provide growth factors and other chemical signals that guide appropriate differentiation of the mesenchymal stem cells, but also to ensure that they remain directed to the appropriate site and are able to emit their appropriate signals and make appropriate cell contacts. This aids healing in three ways: 1) helping the formation of new blood cells from endothelial progenitor cells, which are different type of stem cells that need to be in the regenerative cell mixture or available in the nearby host tissue; 2) preventing programed cell death or apoptosis of cells at the damaged site; and 3) reducing inflammation. ^[39][41][46] Often platelet-rich plasma is used in conjunction with bone-marrow derived stem cells as a matrix which supplies growth factors and the scaffold needed to induce tissue regeneration.^[39][47] Alternatively, adipose tissue contains not only mesenchymal stem cells, but also other diverse types of cells that can provide the microenvironment that supports tissue regeneration without additional factors.^[48][49]

[edit] Sources of autologous (patient-derived) mesenchymal stem cells

Autologous stem cells intended for regenerative therapy are either taken from the patient's bone marrow or from adipose tissue. The number of stem cells applied to the damaged tissue is important for effective therapy. For this reason, stem cells derived from bone marrow aspirates, which are normally in numbers too small to elicit a regenerative effect, are cultured in specialized laboratories to expand their numbers to be in the millions before use in regenerative therapy. ^[41][47] Although adipose-derived tissue also needs processing prior to use in regnerative therapy, the time-consuming culturing like that needed currently for bone marrow derived mesenchymal stem cells, is not required, thus reducing the time between collection and implantation in autologous stem cell treatments.^[50][51] Although mesenchymal stem cells from any source have the potential to differentiate into a diverse range of tissues expert opinions vary as to which source is preferable in particular applications. Some have expressed bone-marrow derived stem cells are particularly preferred for bone, cartilage, ligament, and tendon repair; while others find the ease of collection and the multi-cellular microenvironment already present in adipose-derived stem cell fractions make fat the preferred source. ^[39]

[edit] Currently Available Treatments for Horses and Dogs Suffering from Orthopedic 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.^[41][52] 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^[53][54] 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.^[42][55]

[edit] 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 disorders.

[edit] Rats

Stem cells were tested on rats to see if it would cure the ALS disease (see above under ALS for more information).

[edit] Controversy

There is wide spread controversy over the use of embryonic stem cells. This controversy is over the technique used to create 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. At present there are many alternative sources for stem cells which have achieved considerable success when used as medical therapies. These alternatives do not require the destruction of an embryo, such as the use of umbilical cord blood, milky teeth stem cells, bone marrow stem cells or using genetic stimuli cue skin cells to become toti-potent. It is further argued that such methods have a proven track record of safety and efficacy, eliminating the need to use the more controversial embryonic stem cells.

[edit] Stem cell treatments around the world

[edit] China

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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.

Stem cell therapies provided in China utilize umbilical cord stem 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 claim to 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.

[edit] India

It was reported that Dr. Geeta Shroff of New Delhi treats patients with terminally ill and medically incurable problems. Though having controversial figure, her patients have got very high success rate compared to conventional medicine which shows next to no hope of curing incurable problems.^{[56][57][58][59]} She recently filed a patent with World Intellectual Property Organization^[60] and European Patent Office^[61]

[edit] External links

• Fiona Murray Ph.D., Debora Spar Ph.D. "Bit Player Or Powerhouse? China And Stem-Cell Research", "New England Journal Of Medicine" September 21, 2006 Accessed July 30, 2007
• Clive Cookson "Generous Staffing And Permissive Laws Aid Asia's Largest Stem Cell Effort", "Scientific American" June 27, 2005 Accessed July 30, 2007
• Spare Parts, grown and installed: Finnish cancer patient gets replacement parts grown from his own stem cells.
• Israel21c Israeli scientists reverse brain birth defects using stem cells

[edit] References

v • d • e Cellular differentiation: Stem cells / progenitor cell Sources/types Embryonic stem cells · Adult stem cells · Cancer stem cells Hematopoietic stem cell · Mesenchymal stem cell  · Induced pluripotent stem cells Cell potency Totipotent · Pluripotent · Oligopotent · Multipotent · Unipotent Related articles Stem cell treatments · Stem cell controversy · Stem cell line · Stem cell laws · Stem cell laws and policy in the United States