Stem-cell therapy
Stem-cell therapy uses stem cells to treat or prevent a disease or condition.
Stem-cell therapy has become controversial following developments such as the ability of scientists to isolate and culture embryonic stem cells, to create stem cells using somatic cell nuclear transfer, and their use of techniques to create induced pluripotent stem cells. This controversy is often related to abortion politics and human cloning. Additionally, efforts to market treatments based on transplant of stored umbilical cord blood have been controversial.
Medical uses
For over 90 years, hematopoietic stem cell transplantation (HSCT) has been used to treat people with conditions such as leukemia and lymphoma; this is the only widely practiced form of stem-cell therapy.
Another stem-cell therapy, called Prococvhymal, was conditionally approved in Canada in 2012 for the management of acute graft-vs-host disease in children who are unresponsive to steroids.
The FDA has approved five hematopoietic stem-cell products derived from umbilical cord blood, for the treatment of blood and immunological diseases.
In 2014, the European Medicines Agency recommended approval of limbal stem cells for people with severe limbal stem cell deficiency due to burns in the eye.
Research only
Stem cells are being studied for several reasons. The molecules and exosomes released from stem cells are also being studied in an effort to make medications.
Sources for human stem cells
Most stem cells intended for regenerative therapy are generally isolated either from the patient's bone marrow or from adipose tissue.
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.
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.
As of 2010, there was 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.
In January 2009, the US Food and Drug Administration gave clearance to Geron Corporation for the first clinical trial of an embryonic stem-cell-based therapy on humans. The trial aimed to evaluate the drug GRNOPC1, embryonic stem cell-derived oligodendrocyte progenitor cells, on people 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".
Scientists reported 2012 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 in vitro culture before administration. Re-culturing of MSCs will help in recovering from the shock the cells get during freezing and thawing. Various MSC clinical trials which used cryopreserved product immediately post thaw have failed as compared to those clinical trials which used fresh MSCs.
In drug discovery and biomedical research
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.
Stem cell expansion
To be used for research or treatment applications, large numbers of high-quality stem cells are needed. Thus, it is necessary to develop culture systems which produce pure populations of tissue-specific stem cells in vitro without the loss of stem-cell potential. Two main approaches are taken for this purpose: two-dimensional and three-dimensional cell culture.
Cell culture in two dimensions has been routinely performed in thousands of laboratories worldwide for the past four decades. In two-dimensional platforms, cells are typically exposed to a solid, rigid flat surface on the basal side and to liquid at the apical surface. Inhabiting such a two-dimensional rigid substrate requires a dramatic adaption for the surviving cells because they lack the extracellular matrix that is unique to each cell type which may alter cell metabolism and reduce its functionality.
Three-dimensional cell culture systems may create a biomimicking microenvironment for stem cells, resembling their native three-dimensional extracellular matrix (ECM). Advanced biomaterials have significantly contributed to three-dimensional cell culture systems in recent decades, and more unique and complex biomaterials have been proposed for improving stem-cell proliferation and controlled differentiation. Among them, nanostructured biomaterials are of particular interest because they have the advantage of a high surface-to-volume ratio, and they mimic the physical and biological features of natural ECM at the nanoscale.
Assumed regenerative 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.
Stem cells have been shown to have 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.
Potential applications
Research has been conducted on the effects of stem cells on animal models of brain degeneration, such as in Parkinson's disease, Amyotrophic lateral sclerosis, and Alzheimer's disease.
Healthy adult brains contain neural stem cells, which divide to maintain general stem-cell numbers, or become progenitor cells. In healthy adult laboratory 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 disorders.
Stroke and traumatic brain injury lead to cell death, characterized by a loss of neurons and oligodendrocytes within the brain. Clinical and animal studies have been conducted into the experimental use of stem cells in cases of spinal cord injury.
In 2017, a small-scale study on individuals 60 years or older with aging frailty showed, after intravenous treatment with Mesenchymal stem cells (MSC) from healthy young donors, significant improvements in physical performance measures. MSC helps with the blockade of inflammation by decreasing it, causing the effects of frailty to reverse.
In 2012, stem cells were studied in people with severe heart disease.
Stem-cell therapy for the treatment of myocardial infarction usually makes use of autologous bone marrow stem cells, but other types of adult stem cells may be used, such as adipose-derived stem cells.
Possible mechanisms of recovery include:
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.
In 2004, scientists at King's College London discovered a way to cultivate a complete tooth in mice
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.
Heller has reported success in re-growing cochlea hair cells with the use of embryonic stem cells.
In a 2019 review that looked at hearing regeneration and regenerative medicine, stem cell-derived otic progenitors have the potential to greatly improve hearing.
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 restoring vision.
People with Type 1 diabetes lose the function of insulin-producing beta cells within the pancreas. In a 2007 publication of experiments, scientists have been able to coax embryonic stem cells 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.
As of 2017, use of mesenchymal stem cells (MSCs) derived from adult stem cells was under preliminary research for potential orthopedic applications in bone and muscle trauma, cartilage repair, osteoarthritis, intervertebral disc surgery, rotator cuff surgery, and musculoskeletal disorders, among others.
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.
In 2013, 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).
Criticisms
In 2013, studies of autologous bone marrow stem cells on ventricular function were found to contain "hundreds" of discrepancies.
In 2014, a meta-analysis on stem cell therapy using bone-marrow stem cells for heart disease revealed discrepancies in published clinical trial reports, whereby studies with a higher number of discrepancies showed an increase in effect sizes.
2018 results of the TIME trial, which used a randomized, double-blind, placebo-controlled trial design, concluded that "bone marrow mononuclear cells administration did not improve recovery of LV function over 2 years" in people who had a myocardial infarction.
In 2021, stem cell injections in the US have caused grave infections in at least 20 patients who received umbilical cord blood-derived products marketed as "stem cell treatment".
Veterinary medicine
Research conducted on horses, dogs, and cats has led to the development of stem cell treatments in veterinary medicine which 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 in humans.
Sources of veterinarian 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.
Bone repair
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 treatments 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.
Stem cells have been used to treat degenerative bone diseases in dogs. 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.
Ligament and tendon repair
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.
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.
Osteoarthritis is the main cause of joint pain both in animals and humans. Horses and dogs are most frequently affected by arthritis. Natural cartilage regeneration is very limited. 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 for stem cell treatment of osteoarthritis because of the non-invasive harvesting. 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.
Muscle repair
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.
In 2007, a trial was underway for a patch made of a porous substance onto 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.
2018 research, such as the European nTRACK research project, aims to demonstrate that multimodal nanoparticles can structurally and functionally track stem cell in muscle regeneration therapy. The idea is to label stem cells with gold nano-particles that are fully characterised for uptake, functionality, and safety. The labelled stem cells will be injected into an injured muscle and tracked using imaging systems.
Nervous system repair
Spinal cord injuries are one of the most common traumas brought into veterinary hospitals.
In a study to evaluate the treatment of experimentally induced MS in dogs using laser activated non-expanded adipose derived stem cells. The results showed amelioration of the clinical signs over time confirmed by the resolution of the previous lesions on MRI. Positive migration of the injected cells to the site of lesion, increased remyelination detected by Myelin Basic Proteins, positive differentiation into Olig2 positive oligodendrocytes, prevented the glial scar formation and restored axonal architecture.
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.
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.
Society and culture
Marketing and costs
In the late 1990s and early 2000s, there was an initial wave of companies and clinics offering stem cell therapy, while not substantiating health claims or having regulatory approval.
Costs of stem cell therapies range widely by clinic, condition, and cell type, but most commonly range between $10,000-$20,000.