Stem cell therapy
No stem cell therapies other than bone marrow transplant are widely used. Research is underway to develop various sources for stem cells, and to apply stem cell treatments for neurodegenerative diseases and conditions, diabetes, heart disease, and other conditions.
With the ability of scientists to isolate and culture embryonic stem cells, and with scientists' growing ability to create stem cells using somatic cell nuclear transfer and techniques to created induced pluripotent stem cells, controversy has crept in, both related to abortion politics and to human cloning. Additionally, efforts to market treatments based on transplant of stored umbilical cord blood have proven controversial.
- 1 Medical uses
- 2 Research
- 2.1 Neurodegeneration
- 2.2 Brain and spinal cord injury
- 2.3 Heart
- 2.4 Hematopoiesis (blood-cell formation)
- 2.5 Baldness
- 2.6 Missing teeth
- 2.7 Deafness
- 2.8 Blindness and vision impairment
- 2.9 Diabetes
- 2.10 Orthopaedics
- 2.11 Wound healing
- 2.12 Infertility
- 2.13 HIV/AIDS
- 2.14 Clinical trials
- 3 Other animals
- 3.1 Veterinary applications
- 3.1.1 Potential contributions to veterinary medicine
- 3.1.2 Development of regenerative treatment models
- 3.1.3 Sources of stem cells
- 3.1.4 Stem cells and hard tissue repair
- 3.1.5 Stem cells and orthopedic repairs
- 3.1.6 Stem cells and muscle repairs
- 3.1.7 Stem cells and nervous system repairs
- 3.1.8 Current areas of research
- 3.1 Veterinary applications
- 4 Embryonic stem cell controversy
- 5 Around the world
- 6 See also
- 7 References
- 8 External links
For over 30 years, bone-marrow have been used to treat cancer patients with conditions such as leukaemia and lymphoma; this is the only form of stem cell therapy that is widely practiced. During chemotherapy, most growing cells are killed by the cytotoxic agents. These agents, however, cannot discriminate between the leukaemia 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. The transplanted cells also generate an immune response that helps to kill off the cancer cells; this process can go too far, however, leading to graft vs host disease, the most serious side effect of this treatment.
Another stem cell therapy called Prochymal, was conditionally approved in Canada in 2012 for the management of acute graft-vs-host disease in children who are unresponsive to steroids. It is an allogenic stem therapy based on mesenchymal stem cells (MSCs) derived from the bone marrow of adult donors. MSCs are purified from the marrow, cultured and packaged, with up to 10,000 doses derived from a single donor. The doses are stored frozen until needed.
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). Pharmacological activation of endogenous neural stem cells has been reported to induce neuroprotection and behavioral recovery in adult rat models of neurological disorder.
Brain and spinal cord injury
Stroke and traumatic brain injury lead to cell death, characterized by a loss of neurons and oligodendrocytes within the brain. A small clinical trial was underway in Scotland in 2013, in which stem cells were injected into the brains of stroke patients.
The pioneering work by Bodo-Eckehard Strauer has now been discredited by the identification of hundreds of factual contradictions. Among several clinical trials that have reported that adult stem cell therapy is safe and effective, powerful effects have been reported from only a few laboratories, but this has covered old and recent infarcts as well as heart failure not arising from myocardial infarction. While initial animal studies demonstrated remarkable therapeutic effects, later clinical trials achieved only modest, though statistically significant, improvements. Possible reasons for this discrepancy are patient age, timing of treatment and the recent occurrence of a myocardial infarction. It appears that these obstacles may be overcome by additional treatments which increase the effectiveness of the treatment or by optimizing the methodology although these too can be controversial. Current studies vary greatly in cell procuring techniques, cell types, cell administration timing and procedures, and studied parameters, making it very difficult to make comparisons. Comparative studies are therefore currently needed.
Stem cell therapy for treatment of myocardial infarction usually makes use of autologous bone marrow stem cells (a specific type or all), however other types of adult stem cells may be used, such as adipose-derived stem cells. Adult stem cell therapy for treating heart disease was commercially available in at least five continents as of 2007.
Possible mechanisms of recovery include:
- Generation of heart muscle cells
- Stimulation of growth of new blood vessels to repopulate damaged heart tissue
- Secretion of growth factors
- Assistance via some other mechanism
It may be possible to have adult bone marrow cells differentiate into heart muscle cells.
The first successful integration of human embryonic stem cell derived cardiomyocytes in guinea pigs (mouse hearts beat too fast) was reported in August 2012. The contraction strength was measured four weeks after the guinea pigs underwent simulated heart attacks and cell treatment. The cells contracted synchronously with the existing cells, but it is unknown if the positive results were produced mainly from paracrine as opposed to direct electromechanical effects from the human cells. Future work will focus on how to get the cells to engraft more strongly around the scar tissue. Whether treatments from embryonic or adult bone marrow stem cells will prove more effective remains to be seen.
In 2013 the pioneering reports of powerful beneficial effects of autologous bone marrow stem cells on ventricular function were found to contain "hundreds" of discrepancies. Critics report that of 48 reports there seemed to be just 5 underlying trials, and that in many cases whether they were randomized or merely observational accepter-versus-rejecter, was contradictory between reports of the same trial. One pair of reports of identical baseline characteristics and final results, was presented in two publications as, respectively, a 578 patient randomized trial and as a 391 patient observational study. Other reports required (impossible) negative standard deviations in subsets of patients, or contained fractional patients, negative NYHA classes. Overall there were many more patients published as having receiving stem cells in trials, than the number of stem cells processed in the hospital's laboratory during that time. A university investigation, closed in 2012 without reporting, was reopened in July 2013.
One of the most promising benefits of stem cell therapy is the potential for cardiac tissue regeneration to reverse the tissue loss underlying the development of heart failure after cardiac injury.
Given the apparent inadequacy of unmodified stem cells for heart tissue regeneration, a more promising modern technique involves treating these cells to create cardiac progenitor cells before implantation to the injured area.
Hematopoiesis (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 diagnosed and classified via a subspecialty of pathology known as 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. Further research into this technique should have potential benefits to gene therapy, blood transfusion, and topical medicine.
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, 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).
In 2004, scientists at King's College London discovered a way to cultivate a complete tooth in mice and were able to grow bioengineerd teeth stand-alone in the laboratory. Researchers are confident that the tooth regeneration 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 be grown in a time over three weeks. 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.
Research is ongoing in different fields, alligators which are polyphyodonts grow up to 50 times a successional tooth (a small replacement tooth) under each mature functional tooth for replacement once a year.
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. 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 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.
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.
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.
In January 2012, The Lancet published a paper by Steven Schwartz, at UCLA's Jules Stein Eye Institute, reporting two women who had gone legally blind from macular degeneration had dramatic improvements in their vision after retinal injections of human embryonic stem cells.
Diabetes patients lose the function of insulin-producing beta cells within the pancreas. In recent experiments, scientists have been able to coax embryonic stem cell to turn into beta cells in the lab. In theory if the beta cell is transplanted successfully, they will be able to replace malfunctioning ones in a diabetic patient.
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:
- Transplanted cells should proliferate
- Transplanted cells should differentiate in a site-specific manner
- Transplanted cells should survive in the recipient (prevention of transplant rejection)
- Transplanted cells should integrate within the targeted tissue
- Transplanted cells should integrate into the host circuitry and restore function
Clinical case reports in the treatment 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. 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.
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.
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. 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. Researchers are still investigating different aspects of the "soil" tissue that are conducive to regeneration.
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.
In 2012, oogonial stem cells were isolated from adult mouse and human ovaries and demonstrated to be capable of forming mature oocytes. These cells have the potential to treat infertility.
Destruction of the immune system by the HIV is driven by the loss of CD4+ T cells in the peripheral blood and lymphoid tissues. Viral entry into CD4+ cells is mediated by the interaction with a cellular chemokine receptor, the most common of which are CCR5 and CXCR4.1 Because subsequent viral replication requires cellular gene expression processes, activated CD4+ cells are the primary targets of productive HIV infection. Recently scientists have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC).
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 aimed evaluate the drug GRNOPC1, embryonic stem cell-derived oligodendrocyte progenitor cells, on patients with acute spinal cord injury. The trial was discontinued in November 2011 so that the company could focus on therapies in the "current environment of capital scarcity and uncertain economic conditions". In 2013 biotechnology and regenerative medicine company BioTime (NYSE MKT: BTX) acquired Geron's stem cell assets in a stock transaction, with the aim of restarting the clinical trial.
Cryopreserved Mesenchymal stromal cells (MSCs)
Scientists have reported that MSCs when transfused immediately within few hours post thawing may show reduced function or show decreased efficacy in treating diseases as compared to those MSCs which are in log phase of cell growth(fresh), so cryopreserved MSCs should be brought back into log phase of cell growth in invitro culture before these are administered for clinical trials or experimental therapies, re-culturing of MSCs will help in recovering from the shock the cells get during freezing and thawing. Various clinical trials on MSCs have failed which used cryopreserved product immediately post thaw as compared to those clinical trials which used fresh MSCs [Francois M et al., Cytotherapy.2012;14:147–152].
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. 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. Companion animals can serve as clinically relevant models that closely mimic human disease.
Development of regenerative treatment models
- Stem cells are thought to mediate repair via five primary mechanisms: 1) providing an anti-inflammatory 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.
- 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. 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.
- Stem cells have also been shown to have a low immunogenicity due to the relatively low number of MHC molecules found on their surface. In addition, they have been found to secrete chemokines that alter the immune response and promote tolerance of the new tissue. This allows for allogeneic treatments to be performed without a high rejection risk.
Sources of stem cells
- 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. There are two main categories of stem cells used for treatments: allogeneic stem cells derived from a genetically different donor within the same species and autologous mesenchymal stem cells, derived from the patient prior to use in various treatments. A third category, xenogenic stem cells, or stem cells derived from different species, are used primarily for research purposes, especially for human treatments.
- Most stem cells intended for regenerative therapy are generally isolated either from the patient's bone marrow or from adipose tissue. Mesenchymal stem cells can differentiate into the cells that make up bone, cartilage, tendons, and ligaments, as well as muscle, neural and other progenitor tissues, they have been the main type of stem cells studied in the treatment of diseases affecting these tissues. 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. 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. 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.
- New sources of mesenchymal stem cells are currently being researched, including stem cells present in the skin and dermis which are of interest because of the ease at which they can be harvested with minimal risk to the animal. Hematopoetic stem cells have also been discovered to be travelling in the blood stream and possess equal differentiating ability as other mesenchymal stem cells, again with a very non-invasive harvesting technique.
- There has been more recent interest in the use of extra embryonic mesenchymal stem cells. Research is currently underway to examine the differentiating capabilities of stem cells found in the umbilical cord, yolk sac and placenta of different animals. These stem cells are thought to have more differentiating ability than their adult counterparts, including the ability to more readily form tissues of endodermal and ectodermal origin.
Stem cells and hard tissue repair
- Because of the general positive healing capabilities of stem cells, they have gained interest for the treatment of cutaneous wounds. This is important interest for those with reduced healing capabilities, like diabetics and those undergoing chemotherapy. In one trial, stem cells were isolated from the Wharton’s jelly of the umbilical cord. These cells were injected directly into the wounds. Within a week, full re-epithelialization of the wounds had occurred, compared to minor re-epithelialization in the control wounds. This also showed the capabilities of mesenchymal stem cells in the repair of epidermal tissues.
- Soft palate defects in horses are caused by a failure of the embryo to fully close at the midline during embryogenesis. These are often not found until after they have become worse because of the difficulty in visualizing the entire soft palate. This lack of visualization is thought to also contribute to the low success rate in surgical intervention to repair the defect. As a result, the horse often has to be euthanized. Recently, the use of mesenchymal stem cells has been added to the conventional treatments. After the surgeon has sutured the palate closed, autologous mesenchymal cells are injected into the soft palate. The stem cells were found to be integrated into the healing tissue especially along the border with the old tissue. There was also a large reduction in the number of inflammatory cells present, which is thought to aid in the healing process.
Stem cells and orthopedic repairs
- 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.
- Race horses are especially prone to injuries of the tendon and ligaments. Conventional therapies are very unsuccessful in returning the horse to full functioning potential. Natural healing, guided by the conventional treatments, leads to the formation of fibrous scar tissue that reduces flexibility and full joint movement. Traditional treatments prevented a large number of horses from returning to full activity and also have a high incidence of re-injury due to the stiff nature of the scarred tendon. Introduction of both bone marrow and adipose derived stem cells, along with natural mechanical stimulus promoted the regeneration of tendon tissue. The natural movement promoted the alignment of the new fibers and tendocytes with the natural alignment found in uninjured tendons. Stem cell treatment not only allowed more horses to return to full duty and also greatly reduced the re-injury rate over a three-year period.
- More recently, the use of embryonic stem cells has also been applied to tendon repair. The embryonic stem cells were shown to have a better survival rate in the tendon as well as better migrating capabilities to reach all areas of damaged tendon. The overall repair quality was also higher, with better tendon architecture and collagen formed. There was also no tumor formation seen during the three month experimental period. Long term studies need to be carried out to examine the long term efficacy and risks associated with the use of embryonic stem cells. Similar results have been found in small animals.
- Osteoarthritis is the main cause of joint pain both in animals and humans. Horses and dogs are most frequently affected arthritis. Natural cartilage regeneration is very limited and no current drug therapies are curative, but rather look to reduce the symptoms associated with the degeneration. Different types of mesenchymal stem cells and other additives are still being researched to find the best type of cell and method for long term treatment.
- Adipose-derived mesenchymal cells are currently the most often used because of the non-invasive harvesting. There has been a lot of success recently injecting mesenchymal stem cells directly into the joint. This is a recently developed, non-invasive technique developed for easier clinical use. Dogs receiving this treatment showed greater flexibility in their joints and less pain.
Bone defect repair
- While further studies are necessary to fully characterize the use of cell-based therapeutics for treatment of bone fractures, s
- Bone has a unique and well documented natural healing process that normally is sufficient to repair fractures and other common injuries. Misaligned breaks due to severe trauma, as well as things like tumor resections of bone cancer, are prone to improper healing if left to the natural process alone. Scaffolds composed of natural and artificial components are seeded with mesenchymal stem cells and placed in the defect. Within four weeks of placing the scaffold, newly formed bone begins to integrate with the old bone and within 32 weeks, full union is achieved. Further studies are necessary to fully characterize the use of cell-based therapeutics for treatment of bone fractures.
- Stem cells have also been used to treat degenerative bone diseases. The normally recommended treatment for dogs that have Legg-Calve-Perthes disease is to remove the head of the femur after the degeneration has progressed. Recently, mesenchymal stem cells have been injected directly in to the head of the femur, with success not only in bone regeneration, but also in pain reduction.
Stem cells and muscle repairs
- Stem cells have successfully been used to ameliorate healing in the heart after myocardial infarction in dogs. Adipose and bone marrow derived stem cells were removed and induced to a cardiac cell fate before being injected into the heart. The heart was found to have improved contractility and a reduction in the damaged area four weeks after the stem cells were applied.
- A different trial is underway for a patch made of a porous substance on to which the stem cells are "seeded" in order to induce tissue regeneration in heart defects. Tissue was regenerated and the patch was well incorporated into the heart tissue. This is thought to be due, in part, to improved angiogenesis and reduction of inflammation. Although cardiomyocytes were produced from the mesenchymal stem cells, they did not appear to be contractile. Other treatments that induced a cardiac fate in the cells before transplanting had greater success at creating contractile heart tissue.
- Stem cells have been used recently to hasten the healing of skeletal muscle tears in working dogs. Traditional therapies rely on rest and anti-inflammatory treatments have been shown to permanently reduce the functioning in the muscle. Adipose derived stem cells were injected directly into the tear of the semitendinosus muscle. Physical therapy was also completed during the healing process. Healing was observed much earlier than with traditional methods and the dogs were able to return to full work without any long term muscle damage.
Stem cells and nervous system repairs
- Spinal cord injuries are one of the most common traumas brought into veterinary hospitals. Spinal injuries occur in two ways after the trauma: the primary mechanical damage, and in secondary processes, like inflammation and scar formation, in the days following the trauma. These cells involved in the secondary damage response secrete factors that promote scar formation and inhibit cellular regeneration. Mesenchymal stem cells that are induced to a neural cell fate are loaded on to a porous scaffold and are then implanted at the site of injury. The cells and scaffold secrete factors that counteract those secreted by scar forming cells and promote neural regeneration. Eight weeks later, dogs treated with stem cells showed immense improvement over those treated with conventional therapies. Dogs treated with stem cells were able to occasionally support their own weight, which has not been seen in dogs undergoing conventional therapies.
- Treatments are also in clinical trials to repair and regenerate peripheral nerves. Peripheral nerves are more likely to be damaged, but the effects of the damage are not as widespread as seen in injuries to the spinal cord. Treatments are currently in clinical trials to repair severed nerves, with early success. Stem cells induced to a neural fate injected in to a severed nerve. Within four weeks, regeneration of previously damaged stem cells and completely formed nerve bundles were observed.
- Stem cells are also in clinical phases for treatment in ophthalmology. Hematopoietic stem cells have been used to treat corneal ulcers of different origin of several horses. These ulcers were resistant to conventional treatments available, but quickly responded positively to the stem cell treatment. Stem cells were also able to restore sight in one eye of a horse with retinal detachment, allowing the horse to return to daily activities.
Current areas of research
Stems cells in the lab
- The ability to grow up functional adult tissues indefinitely in culture creates new opportunities for drug research. Researchers are able to grow up differentiated cell lines and then test new drugs on each cell type to examine possible interactions in vitro before performing in vivo studies. This is critical in the development of drugs for use in veterinary research because of the possibilities of species specific interactions. The hope is that having these cell lines available for research use will reduce the need for research animals used because affects on human tissue in vitro will provide insight not normally known before the animal testing phase.
- With the advent of induced pluripotent stem cells (iPSC), treatments being explored and created for the used in endangered low production animals possible. Rather than needing to harvest embryos or eggs, which are limited, the researchers can remove mesenchymal stem cells with greater ease and greatly reducing the danger to the animal due to noninvasive techniques. This allows the limited eggs to be put to use for reproductive purposes only.
Stem cells and conservation
- Stem cells are being explored for use in conservation efforts. Spermatogonial stem cells have been harvested from a rat and placed into a mouse host and fully mature sperm were produced with the ability to produce viable offspring. Currently research is underway to find suitable hosts for the introduction of donor spermatogonial stem cells. If this becomes a viable option for conservationists, sperm can be produced from high genetic quality individuals who die before reaching sexual maturity, preserving a line that would otherwise be lost.
Future clinical uses
- The use of stem cells for the treatment of liver disease in both humans and animals has been the focus of considerable interest. The liver has some natural regenerative properties, but is often insufficient to deal with the extent of some liver diseases. Hepatocytes have been formed from some sources of MSC, but they have not been applied clinically currently. There is a large effort to create stem cells differentiated along the pancreatic line as a possible cure for diabetes, but no line has been well established.
- Mesenchymal stem cells are currently under clinical trials as a possible treatment for graft v. host disease and graft rejection after experiments on various animals showing that allogenic stem cell treatments were not rejected and showed no difference in healing capabilities compared with autologous stem cells. This is being further researched for creating off-the-shelf allogenic stem cell treatments for various aspects in regenerative veterinary medicine. Clinical trials are underway to explore the low immunogenic properties of stem cells and their possible use for treatment of problems with an overactive immune system seen with allergies and autoimmune disorders.
- In recent years, US based stem cell clinics have emerged that treat patients with their own bone marrow or adipose derived adult stem cells as part of clinical trials or FDA authorized same day outpatient IRB programs, most notably for athletes to recover from osteoskeletal (bone, joint and connective tissue) related injuries. This emergence of US based human adult stem cell therapy is discussed by Rudderham in his 2012 article Adult Stem Cell US Therapy.
- The long term impact of these treatments will need to be examined outside of their contribution to medicine. Vast improvements in veterinary medicine has allowed for companion and farm animals to live longer lives. This, however, has contributed to the rise in injury and chronic illness in companion animals. Stem cell treatments, especially for the treatment of orthopedic issues in horses, allows for working animals to return to a normal state of activity at a faster rate with a reduction in the re-injury rate.
Embryonic 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. There is other stem cell research that does not involve the destruction of a human embryo, and such research involves adult stem cells, amniotic stem cells and induced pluripotent stem cells.
Around the world
Stem cell research and treatment was practiced 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. The Western World has scrutinized China for its failed attempts to meet international documentation standards of these trials and procedures.
State-funded companies based in the Shenzhen Hi-Tech Industrial Zone treat the symptoms of numerous disorders with adult stem cell therapy. Development companies 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 of patients with Cerebral Palsy, Alzheimer's, and brain injuries.
Since 2008 many centres and doctors tried a diversity of methods; in Lebanon proliferative and non-proliferative, in-vivo and in-vitro techniques were used. The Regenerative Medicine took also place in Jordan and Egypt.
Stem cell treatment is currently being practiced at a clinical level in Mexico. An International Health Department Permit (COFEPRIS) is required. Authorized centers are found in Tijuana, Guadalajara and Cancun. Currently undergoing the approval process is Los Cabos. This permit allows the use of stem cell.
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.
As of 2013, Thailand still considers Hematopoietic stem cell transplants as experimental. Kampon Sriwatanakul began with a clinical trial in October 2013 with 20 patients. 10 are going to receive stem cell therapy for Type-2 Diabetes and the other 10 will receive stem cell therapy for emphysema. Chotinantakul research on Hematopoietic cells and their role for the hematopoietic system function in homeostasis and immune response.
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).
Other countries where doctors did stem cells research, trials, manipulation, storage, therapy: Brazil, Cyprus, Germany, Italy, Israel, Japan, Philippines, Russia, Switzerland, Turkey, United Kingdom, India and many others.
- Cardiovascular Cell Therapy Research Network (CCTRN)
- Fetal tissue implant
- Human Stem Cells Institute
- Induced pluripotent stem cell
- Induced stem cells
- Ian Murnaghan for Explore Stem Cells. Updated: 16 December 2013 Why Perform a Stem Cell Transplant?
- Bone Marrow Transplantation and Peripheral Blood Stem Cell Transplantation In National Cancer Institute Fact Sheet web site. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2010. Cited August 24, 2010
- Karanes C, Nelson GO, Chitphakdithai P, Agura E, Ballen KK, Bolan CD, Porter DL, Uberti JP, King RJ, Confer DL (2008). "Twenty years of unrelated donor hematopoietic cell transplantation for adult recipients facilitated by the National Marrow Donor Program". Biology of Blood and Marrow Transplantation 14 (9 Suppl): 8–15. doi:10.1016/j.bbmt.2008.06.006. PMID 18721775.
- Malard F, Mohty M. New Insight for the Diagnosis of Gastrointestinal Acute Graft-versus-Host Disease. Mediators Inflamm. 2014;2014:701013. PMID 24733964
- "Prochymal - First Stem Cell Drug Approved". 22 May 2012.
- "A Stem-Cell-Based Drug Gets Approval in Canada". 17 May 2012.
- Cell Basics: What are the potential uses of human stem cells and the obstacles that must be overcome before these potential uses will be realized?. In Stem Cell Information World Wide Web site. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2009. cited Sunday, April 26, 2009
- Neural Stem Cells May Rescue Memory In Advanced Alzheimer's, Mouse Study Suggests
- Vastag B (April 2001). "Stem cells step closer to the clinic: paralysis partially reversed in rats with ALS-like disease". JAMA 285 (13): 1691–3. doi:10.1001/jama.285.13.1691. PMID 11277806.
- Androutsellis-Theotokis A, Leker RR, Soldner F, et al. (August 2006). "Notch signalling regulates stem cell numbers in vitro and in vivo". Nature 442 (7104): 823–6. doi:10.1038/nature04940. PMID 16799564.
- Androutsellis-Theotokis A, Rueger MA, Park DM, et al. (August 2009). "Targeting neural precursors in the adult brain rescues injured dopamine neurons". Proc. Natl. Acad. Sci. U.S.A. 106 (32): 13570–5. doi:10.1073/pnas.0905125106. PMC 2714762. PMID 19628689.
- Androutsellis-Theotokis A, Rueger MA, Mkhikian H, Korb E, McKay RD (2008). "Signaling pathways controlling neural stem cells slow progressive brain disease". Cold Spring Harb. Symp. Quant. Biol. 73: 403–10. doi:10.1101/sqb.2008.73.018. PMID 19022746.
- Ghosh, Pallab (27 May 2013 ) Stroke patients see signs of recovery in stem cell trial BBC News health, Retrieved 27 may 2013
- Kang KS, Kim SW, Oh YH, et al. (2005). "A 37-year-old spinal cord-injured female patient, transplanted of multipotent stem cells from human UC blood, with improved sensory perception and mobility, both functionally and morphologically: a case study". Cytotherapy 7 (4): 368–73. doi:10.1080/14653240500238160. PMID 16162459.
- Team co-headed by researchers at Chosun University, Seoul National University and the Seoul Cord Blood Bank (SCB) Umbilical cord cells 'allow paralysed woman to walk' By Roger Highfield, Science Editor. Last Updated: 1:28AM GMT 30 Nov 2004
- Cummings BJ, Uchida N, Tamaki SJ, et al. (September 2005). "Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice". Proc. Natl. Acad. Sci. U.S.A. 102 (39): 14069–74. doi:10.1073/pnas.0507063102. PMC 1216836. PMID 16172374.
- Strauer, Bodo; Steinhoff G (Sep 2011). "10 years of intracoronary and intramyocardial bone marrow stem cell therapy of the heart: from the methodological origin to clinical practice". J Am Coll Cardiol 58 (11): 1095–1104. doi:10.1016/j.jacc.2011.06.016. PMID 21884944.
- Francis, DP; Mielewczik, M; Zargaran, D; Cole, GD (Jun 26, 2013). "Autologous bone marrow-derived stem cell therapy in heart disease: Discrepancies and contradictions". International journal of cardiology 168 (4): 3381–403. doi:10.1016/j.ijcard.2013.04.152. PMID 23830344. Retrieved 21 July 2013.
- Strauer, BE; Yousef, M; Schannwell, CM (July 2010). "The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study". European journal of heart failure 12 (7): 721–9. doi:10.1093/eurjhf/hfq095. PMID 20576835.
- Yousef, M; Schannwell, CM; Köstering, M; Zeus, T; Brehm, M; Strauer, BE (Jun 16, 2009). "The BALANCE Study: clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction". Journal of the American College of Cardiology 53 (24): 2262–9. doi:10.1016/j.jacc.2009.02.051. PMID 19520249.
- Schannwell CM, Kostering M, Zeus T, Brehm M, Erdmann G, Fleissner T, Yosef M, Kogler G, Wernet P, Strauer BE. (2008). "Hmane autologe Stammzelltransplantation zur Myokardregeneration bei dilatativer Kardiomyopathie (NYHA Stadium II bis III)". Austrian Journal of Cardiology 15 (1): 23–30.
- Orlic D. et al. (2001). "Bone marrow cells regenerate infarcted myocardium". Nature 410 (6829): 701–705. doi:10.1038/35070587. PMID 11287958.
- Kocher, A. A. et al. "Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function" Nature medicine 7, 430-436, doi:10.1038/86498
- Kuswardhani R. A., Soejitno A. (2011). "Bone marrow-derived stem cells as an adjunctive treatment for acute myocardial infarction: a systematic review and meta-analysis". Acta medica Indonesiana 43 (3): 168–177. PMID 21979282.
- Malliaras K., Kreke M., Marban E. (2011). "The stuttering progress of cell therapy for heart disease". Clinical pharmacology and therapeutics 90 (4): 532–541. doi:10.1038/clpt.2011.175. PMID 21900888.
- Ayala-Lugo, A. et al. Age-dependent availability and functionality of bone marrow stem cells in an experimental model of acute and chronic myocardial infarction" Cell transplantation 20, 407-419, doi:10.3727/096368909X519283
- Zhang, Y. et al. "Timing of bone marrow cell therapy is more important than repeated injections after myocardial infarction" Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology 20: 204-212, doi:10.1016/j.carpath.2010.06.007
- Wang, X. et al. "Donor myocardial infarction impairs the therapeutic potential of bone marrow cells by an interleukin-1-mediated inflammatory response. Science translational medicine 3, 100ra190, doi:10.1126/scitranslmed.3002814
- Krishnamurthy P. et al. (2011). "Interleukin-10 deficiency impairs bone marrow-derived endothelial progenitor cell survival and function in ischemic myocardium". Circulation research 109 (11): 1280–1289. doi:10.1161/CIRCRESAHA.111.248369. PMC 3235675. PMID 21959218.
- Paul, A., Srivastava, S., Chen, G., Shum-Tim, D. & Prakash, S. "Functional Assessment of Adipose Stem Cells for Xenotransplantation Using Myocardial Infarction Immunocompetent Models: Comparison with Bone Marrow Stem Cells. Cell biochemistry and biophysics, doi:10.1007/s12013-011-9323-0
- Guinea pig hearts beat with human cells : Nature News & Comment
- Francis, Darrel P. "Autologous bone marrow-derived stem cell therapy in heart disease: Discrepancies and contradictions". Int J Cardiol. Elsevier. Retrieved 6 July 2013.
- Berndt, Christina. "A minefield of contradictions". Suddeutsche Zeitung. Retrieved 6 July 2013.
- Haider, HKh; Ashraf, M (Jun 2005). "Bone marrow stem cell transplantation for cardiac repair.". American journal of physiology. Heart and circulatory physiology 288 (6): H2557–67. doi:10.1152/ajpheart.01215.2004. PMID 15897328.
- Ortic D, Kajstura J, Chimenti S, Jakoniuk I, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001; 410(6829): 701-5.
- Ptaszek LM, Mansour M, Ruskin JN, Chien KR. Towards regenerative therapy for cardiac disease. The Lancet. 2012; 379(9819): 933-942.
- Giarratana MC, Kobari L, Lapillonne H, et al. (January 2005). "Ex vivo generation of fully mature human red blood cells from hematopoietic stem cells". Nat. Biotechnol. 23 (1): 69–74. doi:10.1038/nbt1047. PMID 15619619.
- Archer, Graeme. "Technology". The Daily Telegraph (London). Retrieved May 24, 2010.
- Anglin, Ian. "Scientists Grow Teeth Using Stem Cells". SingularityHUB. Retrieved 31 July 2014.
- Yen AH, Sharpe PT (January 2008). "Stem cells and tooth tissue engineering". Cell Tissue Res. 331 (1): 359–72. doi:10.1007/s00441-007-0467-6. PMID 17938970.
- Stem cell-based biological tooth repair and regeneration
- Wu, Ping; Wu, Xiaoshan; Jiang, Ting-Xin; Elsey, Ruth M.; Temple, Bradley L.; Divers, Stephen J.; Glenn, Travis C.; Yuan, Kuo; Chen, Min-Huey; Widelitz, Randall B.; Chuon, Cheng-Ming (2013). "Specialized stem cell niche enables repetitive renewal of alligator teeth". Proceedings of the National Academy of Sciences of the United States of America 110 (22): E2009–E2018. doi:10.1073/pnas.1213202110. PMC 3670376. PMID 23671090.
- Gene therapy is first deafness 'cure' - health - 14 February 2005 - New Scientist
- Fetal tissue restores lost sight MedicalNewsToday. Article Date: 28 Oct 2004 - 10:00 PDT
- BBC NEWS | England | Southern Counties | Stem cells used to restore vision
-  The University Hospital of New Jersey, 2002
- "Stem Cell Therapy Makes Cloudy Corneas Clear, According To Pitt Researchers". Medical News Today. 13 April 2009. Retrieved 2009-06-04.
- "Embryonic stem cells improve sight of legally blind women". CNN.com. 23 January 2012. Retrieved 2012-01-12.
- Saki N, Jalalifar MA, Soleimani M, Hajizamani S, Rahim F (2013). "Adverse Effect of High Glucose Concentration on Stem Cell Therap". Int J Hematol Oncol Stem Cell Res 7 (3): 34–40. PMC 3913149. PMID 24505533.
- Goldstein, Ron (2007). Embryonic stem cell research is necessary to find a diabetes cure. Greenhaven Press. p. 44.
- Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D (December 2008). "Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells". Med. Hypotheses 71 (6): 900–8. doi:10.1016/j.mehy.2008.06.042. PMID 18786777.
- Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D (2008). "Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells". Pain Physician 11 (3): 343–53. PMID 18523506.
- Centeno CJ, Schultz JR, Cheever M, Robinson B, Freeman M, Marasco W (March 2010). "Safety and complications reporting on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique". Curr Stem Cell Res Ther 5 (1): 81–93. doi:10.2174/157488810790442796. PMID 19951252.
- Wakitani S, Nawata M, Tensho K, Okabe T, Machida H, Ohgushi H (2007). "Repair of articular cartilage defects in the patello-femoral joint with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine defects in five knees". J Tissue Eng Regen Med 1 (1): 74–9. doi:10.1002/term.8. PMID 18038395.
- Gurtner GC, Callaghan MJ, Longaker MT (2007). "Progress and potential for regenerative medicine". Annu. Rev. Med 58: 299–312. doi:10.1146/annurev.med.58.082405.095329. PMID 17076602.
- Richards M, Fong CY, Bongso A (December 2008). "Comparative evaluation of different in vitro systems that stimulate germ cell differentiation in human embryonic stem cells". Fertil. Steril. 93 (3): 986–94. doi:10.1016/j.fertnstert.2008.10.030. PMID 19064262.
- Ledford H (7 July 2009). "Sperm-like cells made from human embryonic stem cells". Nature News. doi:10.1038/news.2009.646.[dead link]
- White, YAR; Woods DC; Takai Y; Ishihara O; Seki H; Tilly JL. (2012). "Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women". Nature Medicine 18 (3): 413–421. doi:10.1038/nm.2669. PMC 3296965. PMID 22366948.
- Allers, Kristinia; Hütter, Gero; Hofmann, Jörg; Loddenkemper, Chrtoph; Rieger, Kathrin; Thiel, Eckhard; Schneider, Thomas (July 14, 2014). "Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation". Blood 117 (10): 2791. doi:10.1182/blood-2010-09-309591. PMID 21148083.
- DiGiusto, David; Stan, Rodica; Krishnan, Amrita; Li, Haitang; Rossi, John; Zaia, John (November 22, 2013). "Development of Hematopoietic Stem Cell Based Gene Therapy for HIV-1 Infection: Considerations for Proof of Concept Studies and Translation to Standard Medical Practice". Viruses 2013 (5): 2898. doi:10.3390/v5112898.
- O'Connell, Claire (January 27, 2012). "Stem cells - where are we now?". The Irish Times.
- "BioTime acquires stem cell assets from Geron, raises $10 million". San Francisco Business Times. January 7, 2013.
- Chen J, Li Y, Wang L, et al. (April 2001). "Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats". Stroke 32 (4): 1005–11. doi:10.1161/01.STR.32.4.1005. PMID 11283404.
- Assmus B, Schächinger V, Teupe C, et al. (December 2002). "Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI)". Circulation 106 (24): 3009–17. doi:10.1161/01.CIR.0000043246.74879.CD. PMID 12473544.
- Murphy JM, Fink DJ, Hunziker EB, Barry FP (December 2003). "Stem cell therapy in a caprine model of osteoarthritis". Arthritis Rheum. 48 (12): 3464–74. doi:10.1002/art.11365. PMID 14673997.
- Sampaolesi M, Blot S, D'Antona G, et al. (November 2006). "Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs". Nature 444 (7119): 574–9. doi:10.1038/nature05282. PMID 17108972.
- Taylor SE, Smith RK, Clegg PD (March 2007). "Mesenchymal stem cell therapy in equine musculoskeletal disease: scientific fact or clinical fiction?". Equine Vet. J. 39 (2): 172–80. doi:10.2746/042516407X180868. PMID 17378447.
- Tecirlioglu RT, Trounson AO (2007). "Embryonic stem cells in companion animals (horses, dogs and cats): present status and future prospects". Reprod. Fertil. Dev. 19 (6): 740–7. doi:10.1071/RD07039. PMID 17714628.
- Koch TG, Betts DH (November 2007). "Stem cell therapy for joint problems using the horse as a clinically relevant animal model". Expert Opin Biol Ther 7 (11): 1621–6. doi:10.1517/14712518.104.22.1681. PMID 17961087.
- Richardson LE, Dudhia J, Clegg PD, Smith R (September 2007). "Stem cells in veterinary medicine—attempts at regenerating equine tendon after injury". Trends Biotechnol. 25 (9): 409–16. doi:10.1016/j.tibtech.2007.07.009. PMID 17692415.
- Csaki C, Matis U, Mobasheri A, Ye H, Shakibaei M (December 2007). "Chondrogenesis, osteogenesis and adipogenesis of canine mesenchymal stem cells: a biochemical, morphological and ultrastructural study". Histochem. Cell Biol. 128 (6): 507–20. doi:10.1007/s00418-007-0337-z. PMID 17922135.
- Kane, Ed (May 2008). Stem cell therapy shows promise for soft-tissue injury, disease. DVM Newsmagazine. 6E-10E.
- Yamada Y, Ueda M, Naiki T, Takahashi M, Hata K, Nagasaka T (2004). "Autogenous injectable bone for regeneration with mesenchymal stem cells and platelet-rich plasma: tissue-engineered bone regeneration". Tissue Eng. 10 (5–6): 955–64. doi:10.1089/1076327041348284. PMID 15265313.
- Singec I, Jandial R, Crain A, Nikkhah G, Snyder EY (2007). "The leading edge of stem cell therapeutics". Annu. Rev. Med. 58: 313–28. doi:10.1146/annurev.med.58.070605.115252. PMID 17100553.
- Zachos TA, Smith TJ (September 2008). Use of adult stem cells in clinical orthopedics. DVM Newsmagazine. 36-39.
- Walter Brehm (2012). "Stem cell-based tissue engineering in veterinary orthopaedics". Cell Tissue Research 347 (3): 677–688. doi:10.1007/s00441-011-1316-1. PMID 22287044.
- Young RG, Butler DL, Weber W, Caplan AI, Gordon SL, Fink DJ (July 1998). "Use of mesenchymal stem cells in a collagen matrix for Achilles tendon repair". J. Orthop. Res. 16 (4): 406–13. doi:10.1002/jor.1100160403. PMID 9747780.
- Awad HA, Butler DL, Boivin GP, et al. (June 1999). "Autologous mesenchymal stem cell-mediated repair of tendon". Tissue Eng. 5 (3): 267–77. doi:10.1089/ten.1999.5.267. PMID 10434073.
- Bruder SP, Kraus KH, Goldberg VM, Kadiyala S (July 1998). "The effect of implants loaded with autologous mesenchymal stem cells on the healing of canine segmental bone defects". J Bone Joint Surg Am 80 (7): 985–96. PMID 9698003.
- Kraus KH, Kirker-Head C (April 2006). "Mesenchymal stem cells and bone regeneration". Vet Surg 35 (3): 232–42. doi:10.1111/j.1532-950X.2006.00142.x. PMID 16635002.
- Daniela Gattegno-Ho (2012). "Stem cells and veterinary medicine: Tools to understand diseases and enable tissue regeneration and drug discovery". The Veterinary Journal 191 (1): 19–27. doi:10.1016/j.tvj.2011.08.007. PMID 21958722.
- Nathan S, Das De S, Thambyah A, Fen C, Goh J, Lee EH (August 2003). "Cell-based therapy in the repair of osteochondral defects: a novel use for adipose tissue". Tissue Eng. 9 (4): 733–44. doi:10.1089/107632703768247412. PMID 13678450.
- Fraser JK, Wulur I, Alfonso Z, Hedrick MH (April 2006). "Fat tissue: an underappreciated source of stem cells for biotechnology". Trends Biotechnol. 24 (4): 150–4. doi:10.1016/j.tibtech.2006.01.010. PMID 16488036.
- Nakagami H, Morishita R, Maeda K, Kikuchi Y, Ogihara T, Kaneda Y (April 2006). "Adipose tissue-derived stromal cells as a novel option for regenerative cell therapy". J. Atheroscler. Thromb. 13 (2): 77–81. doi:10.5551/jat.13.77. PMID 16733294.[dead link]
- Bong Wook Park (2012). "Peripheral nerve regeneration using autologous porcine skin-derived mesenchymal stem cells". Journal of Tissue Engineering and Regenerative Medicine 6 (2): 113–124. doi:10.1002/term.404. PMID 21337707.
- Gabriella Marfe (2012). "Blood derived stem cells: An ameliorative therapy in veterinary ophthalmology". Journal of Cellular Physiology 227 (3): 1250–1256. doi:10.1002/jcp.22953. PMID 21792938.
- Omid Azari (2011). "Effects of transplanted mesenchymal stem cells isolated from Wharton's jelly of caprine umbilical cord on cutaneous wound healing; histopathological evaluation". Veterinary Research Communications 35 (4): 211–222. doi:10.1007/s11259-011-9464-z. PMID 21340694.
- Carstanjen B, Desbois C, Hekmati M, Behr L (2006). "Successful engraftment of cultured autologous mesenchymal stem cells in a surgically repaired soft palate defect in an adult horse". The Canadian Journal of Veterinary Research 70 (2): 143–147. PMC 1410720. PMID 16639947.
- Black LL, Gaynor J, Adams C, et al. (2008). "Effect of intraarticular injection of autologous adipose-derived mesenchymal stem and regenerative cells on clinical signs of chronic osteoarthritis of the elbow joint in dogs". Vet. Ther. 9 (3): 192–200. PMID 19003780.
- Nixon AJ, Dahlgren LA, Haupt JL, Yeager AE, Ward DL (July 2008). "Effect of adipose-derived nucleated cell fractions on tendon repair in horses with collagenase-induced tendinitis". Am. J. Vet. Res. 69 (7): 928–37. doi:10.2460/ajvr.69.7.928. PMID 18593247.
- Annalisa Guercio (2012). "Production of canine mesenchymal stem cells from adipose tissue and their application in dogs with chronic osteoarthritis of the humeroradial joints". Cell Biology International 36 (2): 189–194. doi:10.1042/CBI20110304. PMID 21936851.
- I Ribitsch (2010). "Basic Science and Clinical Application of Stem Cells in Veterinary Medicine". Advanced Biochemical Engineering and Biotechnology 123: 219–263. doi:10.1007/10_2010_66. ISBN 978-3-642-16050-9.
- Ung Kim (2011). "Homing of adipose-derived stem cells to radiofrequency catheter ablated canine atrium and differentiation into cardiomyocyte-like cells". International Journal of Cardiology 146 (3): 371–378. doi:10.1016/j.ijcard.2009.07.016. PMID 19683815.
- Yen Chang (2007). "Tissue regeneration observed in a basic fibroblast growth factor–loaded porous acellular bovine pericardium populated with mesenchymal stem cells". Surgery for Acquired Cardiovascular Disease 134: 65–73. doi:10.1016/j.jtcvs.2007.02.019.
- S. Gary Brown, Robert J Harman, & Linda L Black (2012). "Adipose-derived stem cell therapy for severe muscle tears in working German shepherds: Two case reports". Stem Cell Discovery 2 (2): 41–44. doi:10.4236/scd.2012.22007.
- Sung Su Park et al. (2012). "Functional recovery after spinal cord injury in dogs treated with a combination of Matrigel and neural-induced adipose-derived mesenchymal Stem cells". Cytotherapy 14 (5): 584–597. doi:10.319/14653249.2012.658913. PMID 22348702.
- Hak-Hyun Ryu (2009). "Functional recovery and neural differentiation after transplantation of allogenic adipose-derived stem cells in a canine model of acute spinal cord injury". Journal of Veterinary Science 10 (4): 273–284. doi:10.4142/jvs.2009.10.4.273. PMC 2807262. PMID 19934591.
- Hidetaka Nishida et al. (2012). Veterinary Surgery 00: 1–6. doi:10.111/j.1532-950X.2011.00959.x.
- I. Dobrinski and A.J. Travis (2007). "Germ cell transplantation for the propagation of companion animals, non-domestic and endangered species". Reproduction, Fertility, and Development 19: 732–739. doi:10.1071/RD07036.
- Health, Wellness, Nutrition and Anti-Aging Integrative Medicine Experts & Information - Superior Raw Super Food Supplements - Online Wellness Community
- Mlsna, Lucas J. (2010). "Stem Cell Based Treatments and Novel Considerations for Conscience Clause Legislation". Indiana Health Law Review (United States: Indiana University Robert H. McKinney School of Law) 8 (2): 471–496. ISSN:1549-3199. LCCN:2004212209. OCLC:54703225.
- Dobkin BH, Curt A, Guest J (March 2006). "Cellular transplants in China: observational study from the largest human experiment in chronic spinal cord injury". Neurorehabil Neural Repair 20 (1): 5–13. doi:10.1177/1545968305284675. PMID 16467274.
- "Stem cells tailored to patients". BBC News. May 20, 2005. Retrieved May 24, 2010.
- Chotinantakul K and Leeanansaksiri W (June 2012). "Hematopoietic stem cell development, niches, and signaling pathways". PubMed 10 (6): 12–16. doi:10.1155/2012/270425. PMID 22900188.
- 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)
- BioTime web site
- Clive Cookson "Generous Staffing And Permissive Laws Aid Asia's Largest Stem Cell Effort", "Scientific American" June 27, 2005. (Accessed July 30, 2007)
- Stem cell research & therapy: types of stem cells and their current uses