Stem cell treatments

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Stem cell treatments are a type of cell therapy 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.

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, among others.[2]

Stem cells play an important role in current research in developing new medical techniques. 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.[3] 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.[4] Researchers are still investigating different aspects of the "soil" tissue that are conducive to regeneration.[5]

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.[6]

Contents

[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 unfortunate 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. In all current stem cell treatments obtaining stem cells from a matched donor is preferable to using the patients own. If (always as a last resort and usually because no matched donor can be found) it is deemed necessary for the patients own stem cells to be used and the patient has not stored their own collection of stem cells (umbilical cord blood), bone marrow samples must therefore be removed before chemotherapy, and are re-injected afterwards.[citation needed]

[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.

Recently, results from research conducted in rats subjected to stroke, suggested that administration of drugs to increase the stem cell division rate and direct the survival and differentiation of newly formed cells could be successful. In the study referenced below, biological drugs were administered after stroke to activate two key steps in the reparative process. Findings from this study seem to support a new strategy for the treatment of stroke using a simple elegant approach, aimed at directing recovery from stroke by potentially protecting and/or regenerating new tissue. The authors found that, within weeks, recovery of brain structure is accompanied by recovery of lost limb function suggesting the potential for development of a new class of stroke therapy or brain injury therapy in humans.[citation needed]

[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.[7] 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.[8]

[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. The team was co-headed by researchers at Chosun University, Seoul National University and the Seoul Cord Blood Bank (SCB). 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.[9][10][11][12]

The Korean researchers have followed up on their original work. The original treatment was conducted in November 2004. On April 18, 2005, the researchers announced that they will be conducting a second treatment on the woman.[13] The researchers have followed up with a case study write-up on their work. It is located in the journal Cytotherapy.[14]

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.

[edit] Heart damage

Several clinical trials targeting heart disease have shown that adult stem cell therapy is safe and effective. Adult stem cell therapy for heart disease was commercially available on at least five continents at the last count (2007).

[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 antigen. However, this system it 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. Lymphomas and hematopoietic cancers to HIC, the disruption of cell homeostasis within the immune system commonly leads to disease. The specificity of one's immune cell repertoire, which allows it to recognize foreign antigen, causes 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.

In December 2004, a team of researchers led by Dr. Luc Douay at the University of Paris developed a method to produce large numbers of red blood cells. The Nature Biotechnology paper, entitled Ex vivo generation of fully mature human red blood cells, describes the process: precursor red blood cells, called hematopoietic stem cells, 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. 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. Hair Cloning Nears Reality as Baldness Cure (WebMD November 2004)

[edit] 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, which would be expected to take two months to grow.[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.

It's estimated that it may take until 2009 before the technology is widely available to the general public, but the genetic research scientist behind the technique, Professor Paul Sharpe of King's College, estimated the method could be ready to test on patients by 2007.[17] His startup company, Odontis, fully expects to offer tooth replacement therapy by year 2015-2018[18]

In 2005, Cryopraxis a stem cell bank in Brazil, collected baby tooth stem cells and harvested different types of differentiated cell types including neurons. This technology may one day make baby teeth a good source of stem cells.

In the next three years, Paul Sharpe hopes to identify more-accessible stem cells that may be able to form not only teeth, but also--and more importantly--roots. [19]

[edit] Deafness

There has been success in re-growing cochlea hair cells with the use of stem cells.[20]

[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.[21] 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.[22]

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 carried out in 1905 on a cornea by Dr. Eduard Zirm. The recipient was Alois Gloger, a labourer who had been blinded in an accident. 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 which causes vision impairment and has no known cure even after corneal transplant. It is hoped that stem cell research will one day provide a cure to such debilitating corneal disorders.

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.[23]

[edit] ALS (Lou Gehrig's Disease)

In the April 4, 2001 edition of JAMA (Vol. 285, 1691-1693),[24] Drs. Gearhart and Kerr of Johns Hopkins University used stem cells to cure rats of an ALS-like disease. The rats were injected with a virus to kill the spinal cord motor nerves related to leg movement. Dr. Gearhart and Dr. Kerr then injected the spinal cords of the rats with stem cells. 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.

[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.[25]

[edit] Neural and behavioral birth defects

A team of researchers from the Hebrew University of Jerusalem-Hadassah Medical 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. The work of Yanai and his associates was presented at the second International Stem Cell Meeting in Tel Aviv in the spring of 2008 and is expected to be presented and published in 2009 at the seventh annual meeting of the International Society for Stem Cell Research in Barcelona, Spain. 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.[26]

[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 on high field MRI evidence of increased cartilage and meniscus volume in human clinical subjects.[27] [28] 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.[29] The first commercial application of culture expanded, adult stem cells in the US focuses on orthopedic treatment.[30]

[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.[31][32][33][34] 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.[35] Companion animals may be superior models than typical mouse models for human disease. [36][37]

[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.[38] [39][40]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.[41][42]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.[43] [44][45]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.[46] [47]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.[46] [47]Treating tendon and ligament injuries in horses using stem cells, whether derived from adipose tissue or bone-marrow, has support in the veterinary literature.[48][49]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.[50][51][52]

[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.[53][47][45][54] 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. [53][45][47]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.[45][54] 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.[55][56][43]

[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. [54][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.[57][58] 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.[45][43][44]

[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.[47][59]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.[43][44]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.[43] Over 3000 privately-owned horses and dogs have been treated with autologous adipose-derived stem cells.[43] 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[60][61] 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.[62][63]

[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.[64]

[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 based on moral or religious objections. Others point to the success already being achieved with stem cell therapy that does not result in the destruction of a embryo, such as the use of cord blood cells to treat spinal cord injury paralysis or recent research in turning skin fibroblasts into embryonic stem cell-like cells, and argue that research should be aimed in those avenues with a proven safety and efficacy.

[edit] Recent updates

[edit] Some scientists see shift in stem cell hopes

It was reported in the New York Times (14 August 2006), by Nicholas Wade, that some scientists see a shift in stem cell hopes. Several mentioned that the main role of stem cells was in research. Many no longer see cell therapy as the first goal of the research, parting company with those whose near-term expectations for cell therapy remain high.[65]

Thomas M. Jessell, a neurobiologist at Columbia University said "Many of us feel that for the next few years the most rational way forward is not to push stem cell therapies."[65]

In America, Barrack Obama has lifted the federal funding ban on stem cell research.[66]

[edit] Stem Cell Research and Treatment in China

Stem cell research and treatment is actively practiced in China. State funded Chinese 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.

Chinese stem cell research has not been restricted by the ethical dilemmas and legislative gridlock surrounding the procurement and use of human embryonic stem cells in other developed nations such as the US, UK, and Australia. These issues have also hampered the development of adult stem cell research and therapy, as unrelated a cellular origin as they may have. Most stem cell therapies provided in China utilize umbilical cord stem cells (drawn from Wharton's jelly) donated from live births. The stem cells are then expanded in centralized blood banks. Cells are delivered to patients via IV, spinal epidural, subcutaneous injection or transplantation.

While anecdotal evidence of secondary adult stem cell activity has existed for several decades alongside bone marrow transplant therapies, "off-label" uses for stem cells are strictly forbidden in the USA. There, protocols for proposed treatments are described and enforced by the Food and Drug Administration (FDA). In America, the period between laboratory experimentation and clinical treatment can be decades long. Researchers actively treating patients with experimental therapies outside of carefully monitored clinical trials can be subject to harsh disciplinary action by their institutions. The Chinese Ministry of Health has already accepted the use of stem cell therapy for many disorders. After years of practice, stem cell therapy is no longer considered new or dangerous in China and is regularly used by the Chinese in the treatment of the degenerative effects of Multiple sclerosis and Parkinson's disease. International "Medical Tourists" are among the thousands of patients treated in China every year for disorders the patients' home country's medical professionals offer no treatment.

[edit] External links

[edit] References

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