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Culture of [[human embryonic stem cell]]s in mitotically inactivated porcine ovarian fibroblasts (POF) causes differentiation into [[germ cell]]s (precursor cells of oocytes and spermatozoa), as evidenced by [[gene expression]] analysis.<ref>{{cite journal |author=Richards M, Fong CY, Bongso A |title=Comparative evaluation of different in vitro systems that stimulate germ cell differentiation in human embryonic stem cells |journal=Fertil. Steril. |volume= 93|issue= 3|pages= 986–94|date=December 2008 |pmid=19064262 |doi=10.1016/j.fertnstert.2008.10.030 |url=}}</ref>
Culture of [[human embryonic stem cell]]s in mitotically inactivated porcine ovarian fibroblasts (POF) causes differentiation into [[germ cell]]s (precursor cells of oocytes and spermatozoa), as evidenced by [[gene expression]] analysis.<ref>{{cite journal |author=Richards M, Fong CY, Bongso A |title=Comparative evaluation of different in vitro systems that stimulate germ cell differentiation in human embryonic stem cells |journal=Fertil. Steril. |volume= 93|issue= 3|pages= 986–94|date=December 2008 |pmid=19064262 |doi=10.1016/j.fertnstert.2008.10.030 |url=}}</ref>


Human embryonic stem cells have been stimulated to form [[Spermatozoon]]-like cells, yet still slightly damaged or malformed.<ref>{{cite journal |author=Ledford H |title=Sperm-like cells made from human embryonic stem cells |journal=Nature News |date=7 July 2009 |doi=10.1038/news.2009.646 |url=http://www.nature.com/news/2009/070709/full/news.2009.646.html}} {{Dead link|date=July 2010}}</ref> It could potentially treat [[azoospermia]].
Human embryonic stem cells have been stimulated to form [[Spermatozoon]]-like cells, yet still slightly damaged or malformed.<ref>{{cite journal|author=Ledford H |title=Sperm-like cells made from human embryonic stem cells |journal=Nature News |date=7 July 2009 |doi=10.1038/news.2009.646 |url=http://www.nature.com/news/2009/070709/full/news.2009.646.html |deadurl=yes |archiveurl=https://web.archive.org/20110509035545/http://www.nature.com:80/news/2009/070709/full/news.2009.646.html |archivedate=9 May 2011 }}</ref> It could potentially treat [[azoospermia]].


In 2012, oogonial stem cells were isolated from adult mouse and human ovaries and demonstrated to be capable of forming mature oocytes.<ref name="pmid22366948">{{cite journal|last=White|first=YAR|author2=Woods DC |author3=Takai Y |author4=Ishihara O |author5=Seki H |author6=Tilly JL. |title=Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women|journal=Nature Medicine|year=2012|volume=18|issue=3|pages=413–421|doi=10.1038/nm.2669|pmid=22366948|pmc=3296965}}</ref> These cells have the potential to treat infertility.
In 2012, oogonial stem cells were isolated from adult mouse and human ovaries and demonstrated to be capable of forming mature oocytes.<ref name="pmid22366948">{{cite journal|last=White|first=YAR|author2=Woods DC |author3=Takai Y |author4=Ishihara O |author5=Seki H |author6=Tilly JL. |title=Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women|journal=Nature Medicine|year=2012|volume=18|issue=3|pages=413–421|doi=10.1038/nm.2669|pmid=22366948|pmc=3296965}}</ref> These cells have the potential to treat infertility.

Revision as of 15:04, 14 January 2016

This article is about the medical therapy. For the cell type, see Stem cell.

Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition.

Bone marrow transplant is the most widely used stem-cell therapy, but some therapies derived from umbilical cord blood are also in use. 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 create 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 been controversial.

Medical uses

Further information: Hematopoietic stem cell transplantation

For over 30 years, bone marrow has 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.[1][2][3] 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.[4]

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.[5] 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.[6]

The FDA has approved five hematopoietic stem-cell products derived from umbilical cord blood, for the treatment of blood and immunological diseases.[7]

In 2014, the European Medicines Agency recommended approval of Holoclar, a treatment involving stem cells, for use in the European Union. Holoclar is used for people with severe limbal stem cell deficiency due to burns in the eye.[8]

Research

Diseases and conditions where stem cell treatment is promising or emerging.

Neurodegeneration

Research has been conducted to learn whether stem cells may be used to treat brain degeneration, such as in Parkinson's, Amyotrophic lateral sclerosis, and Alzheimer's disease.[9][10][11]

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.[12][13][14]

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.[15]

Clinical and animal studies have been conducted into the use of stem cells in cases of spinal cord injury.[16][17][18]

Heart

The pioneering work[19] by de [Bodo-Eckehard Strauer] has now been discredited by the identification of hundreds of factual contradictions.[20] 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[21] and recent[22] infarcts as well as heart failure not arising from myocardial infarction.[23] While initial animal studies demonstrated remarkable therapeutic effects,[24][25] later clinical trials achieved only modest, though statistically significant, improvements.[26][27] Possible reasons for this discrepancy are patient age,[28] timing of treatment[29] and the recent occurrence of a myocardial infarction.[30] It appears that these obstacles may be overcome by additional treatments which increase the effectiveness of the treatment[31] 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.[32] Adult stem cell therapy for treating heart disease was commercially available in at least five continents as of 2007.[citation needed]

Possible mechanisms of recovery include:[9]

  • 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.[9]

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.[33]

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.[34] Critics report that of 48 reports there seemed to be just five 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.[35]

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.[36]

Initially, the observed improvements were attributed to a transdifferentiation of BM-MSCs into cardiomyocyte-like cells.[24] 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.[37]

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.[citation needed]

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.[38] Further research into this technique should have potential benefits to gene therapy, blood transfusion, and topical medicine.

Baldness

Hair follicles also contain stem cells, and some researchers predict these follicle stem cells may lead to successes in treating baldness through activation of progenitor stem 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.

Missing teeth

In 2004, scientists at King's College London discovered a way to cultivate a complete tooth in mice[39] and were able to grow bioengineered 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 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.[40] 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.[41][42]

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.[43]

Deafness

Heller has reported success in re-growing cochlea hair cells with the use of embryonic stem cells.[44]

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.[45] 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.[46]

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

The University Hospital of New Jersey reports that the success rate for growth of new cells from transplanted stem cells varies from 25 percent to 70 percent.[47]

In 2014, researchers demonstrated that stem cells collected as biopsies from donor human corneas can prevent scar formation without provoking a rejection response in mice with corneal damage.[48]

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.[49]

In June 2015, the Stem Cell Ophthalmology Treatment Study (SCOTS), the largest adult stem cell study in ophthalmology ( www.clinicaltrials.gov NCT # 01920867) published initial results on a patient with optic nerve disease who improved from 20/2000 to 20/40 following treatment with bone marrow derived stem cells.[50]

Diabetes

Diabetes patients lose the function of insulin-producing beta cells within the pancreas.[51] 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.[52]

Transplantation

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:[9]

  • 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

Orthopaedics

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.[53][54] 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.[55]

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.[56]

Wound healing

Stem cells can also be used to stimulate the growth of human tissues. In an adult, wounded tissue is most often replaced by scar tissue, which is characterized in the skin by disorganized collagen structure, loss of hair follicles and irregular vascular structure. In the case of wounded fetal tissue, however, wounded tissue is replaced with normal tissue through the activity of stem cells.[57] 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.[57] Researchers are still investigating different aspects of the "soil" tissue that are conducive to regeneration.[57]

Infertility

Culture of human embryonic stem cells in mitotically inactivated porcine ovarian fibroblasts (POF) causes differentiation into germ cells (precursor cells of oocytes and spermatozoa), as evidenced by gene expression analysis.[58]

Human embryonic stem cells have been stimulated to form Spermatozoon-like cells, yet still slightly damaged or malformed.[59] It could potentially treat azoospermia.

In 2012, oogonial stem cells were isolated from adult mouse and human ovaries and demonstrated to be capable of forming mature oocytes.[60] These cells have the potential to treat infertility.

HIV/AIDS

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.[61] 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).[62]

Clinical trials

Further information: Human embryonic stem cells clinical trials

GRNOPC1

On 23 January 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".[63] In 2013 biotechnology and regenerative medicine company BioTime (AMEX: BTX) acquired Geron's stem cell assets in a stock transaction, with the aim of restarting the clinical trial.[64]

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.[65]

Other animals

Veterinary applications

Potential contributions to veterinary medicine

Research currently conducted on horses, dogs, and cats can benefit the development of stem cell treatments in veterinary medicine and can target a wide range of injuries and diseases such as myocardial infarction, stroke, tendon and ligament damage, osteoarthritis, osteochondrosis and muscular dystrophy both in large animals, as well as humans.[66][67][68][69] 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.[70] Companion animals can serve as clinically relevant models that closely mimic human disease.[71][72]

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.[73][74]
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.[75][76] 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.[75][76][77][78]
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.[79]

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.[80][81][82] There are two main categories of stem cells used for treatments: allogeneic stem cells derived from a genetically different donor within the same species[78][83] and autologous mesenchymal stem cells, derived from the patient prior to use in various treatments.[75] A third category, xenogenic stem cells, or stem cells derived from different species, are used primarily for research purposes, especially for human treatments.[84]
Most stem cells intended for regenerative therapy are generally isolated either from the patient's bone marrow or from adipose tissue.[76][78] 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.[81][85] 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.[76][78] 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.[86][87] 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.[75]
New sources of mesenchymal stem cells are 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.[88] 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.[89]
There has been more recent interest in the use of extra embryonic mesenchymal stem cells. Research is 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.[79]

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 showed the capabilities of mesenchymal stem cells in the repair of epidermal tissues.[90]
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.[91]

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.[92][93]
Tendon repair
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.[79]
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.[79] Similar results have been found in small animals.[79]
Joint repair
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.[79]
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.[94]
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.[95] Further studies are necessary to fully characterize the use of cell-based therapeutics for treatment of bone fractures.
Stem cells have 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.[95]

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.[96]
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.[97]
Stem cells have been used 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.[98]

Stem cells and nervous system repairs

Spinal cord injuries are one of the most common traumas brought into veterinary hospitals.[95] 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.[99][100][101]
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.[88]
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.[89]

Current areas of research

Stems cells in the lab
The ability to grow up functional adult tissues indefinitely in culture through Directed differentiation 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 effects on human tissue in vitro will provide insight not normally known before the animal testing phase.[84]
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.[84]
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.[102]
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.[95] 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.[95]
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.[79] 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.[84]
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.[103]
The long-term impact of these treatments will need to be examined outside of their contribution to medicine.[79] 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.[84] 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.[79]

Embryonic stem-cell controversy

Main article: Stem-cell controversy

There is widespread controversy over the use of human embryonic stem cells. This controversy primarily targets the techniques used to derive new embryonic stem cell lines, which often requires the destruction of the blastocyst. Opposition to the use of human embryonic stem cells in research is often based on philosophical, moral or religious objections.[104] 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

China

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.[105]

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.[citation needed]

Middle East

Since 2008 many universities, centers and doctors tried a diversity of methods; in Lebanon proliferation for stem cell therapy, in-vivo and in-vitro techniques were used, Thus this country is considered the launching place of the Regentime[106] procedure. http://www.researchgate.net/publication/281712114_Treatment_of_Long_Standing_Multiple_Sclerosis_with_Regentime_Stem_Cell_Technique The regenerative medicine also took place in Jordan and Egypt.[citation needed]

Mexico

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.[citation needed]

South Korea

In 2005, South Korean scientists claimed to have generated stem cells that were tailored to match the recipient. Each of the 11 new stem cell lines was developed using somatic cell nuclear transfer (SCNT) technology. The resultant cells were thought to match the genetic material of the recipient, thus suggesting minimal to no cell rejection.[107]

Thailand

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's research is on Hematopoietic cells and their role for the hematopoietic system function in homeostasis and immune response.[108]

Ukraine

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

Other countries

Other countries where doctors did stem cells research, trials, manipulation, storage, therapy: Brazil, Cyprus, Germany, Italy, Israel, Japan, Pakistan, Philippines, Russia, Switzerland, Turkey, United Kingdom, India and many others.

See also

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