Stem Cells in Therapeutics and Research



Stem cells are now a major part of what is often referred to as regenerative medicine. There are an increasing number of stem cell therapies being researched and thousands of clinical trials. Every cell lineage and nearly every common disease is being evaluated for therapy opportunities. Several therapies are discussed here to illustrate how stem cells are being used, the problems and considerations, and current progress.

In addition to being used in clinical studies, stem cells have been become a major research tool for understanding animal and human development and cell biology. Stem cell models are starting to provide detailed information about all aspects of function in normal and diseased cells and tissues.

Related Topics: Isolation and Maintenance of Stem Cells, Differentiation of Stem Cells, Analysis of Stem Cells, and Transfection and Transduction of Stem Cells.

Transplantation of Stem Cells

Clinical trials involving transplantation of stem cells into the body entail assessment of either tissue repair and/or restoration of function. An example of repair is transplantation of stem cells after spinal cord injury, and an example of restoration of function is the transplantation of stem cells into blind eyes to partially restore vision.

Characteristics of Transplanted Stem Cells

There are a number of requirements for a successful stem cell therapy. Transplanted stem cells should have the following characteristics:

  • Easy to obtain and can readily be sorted and characterized
  • Will survive in the body, remaining viable and not trigger a strong immune response
  • Able to proliferate, preferably mostly in the target tissue
  • Can differentiate into one or more cell types present in the target tissue
  • Can integrate into the targeted tissue
  • Engrafted cells function appropriately
  • Will at least partially restore function and/or repair damaged area

One of the reasons that mesenchymal stem cells (MSCs) are currently used in many clinical trials is that in addition to being present in many tissues in the body, they can home to areas of inflammation. This helps with targeting the stem cells to an area in need of repair and is an advantage when the target area is difficult to access directly, or when local access will cause damage such as ossification.

Bone Marrow Replacement

The first stem cell therapies were bone marrow replacement for patients with blood cancers such as leukemia or multiple myeloma. The first bone marrow transplants were in the late 1950s. After destruction of the patient’s diseased bone marrow, new cells are introduced to the body. Although the infused cells can be cells sourced from the patient (autologous), they are usually heterologous, from a donor with a closely matching human leukocyte antigen (HLA) type. Even with a close match, there is some level of graft-versus-host disease (GVHD).

Repair of Damaged Heart Tissue

Heart disease was one of the first major areas of research for stem cell therapy because cardiac disease is a major health burden, typically affecting adult patients (making informed consent less complicated), and access to the heart is relatively easy via catheter; furthermore, the innate repair mechanisms of the adult heart are relatively ineffective in restoring function.

A heart attack (myocardial infarction) causes an interruption of blood supply to part of the heart. The reduced blood flow (ischemia) results in oxygen levels dropping in heart tissue. The lack of oxygen, and frequently the return of oxygen (reperfusion – which triggers inflammation and oxidative damage), can produce an area with injured and dead heart muscle. Usually, the heart will partially repair the damaged area, mainly by fibroblasts. However, infarct-stimulated fibroblasts form noncontractile scar tissue, making the heart locally stiff and unable to beat efficiently in that area, often leading to cardiac hypertrophy, arrhythmias, and potentially congestive heart failure.

For successful stem cell therapy, introduced cells must be able to functionally differentiate into the mature heart cells. Stem cells first need to become beating cardiomyocytes that are then functionally integrated into the myocardium. Additionally, stem cells should be involved in the regrowth of both blood vessels and cells of the cardiac conduction system in the damaged area.

The effectiveness of stem cell therapies in human heart have varied, with most only showing small changes in functional measurement. The functional regeneration of heart tissues in primates using human embryonic stem cells (hESCs) was recently reported (Chong et al. 2014). The stem cells integrated into the damaged tissue, formed fibers, and beat synchronously with the recipient heart. At this point, there exists no standard protocol for the type of stem cells used, amplification or pretreatment of the cells, the quantity and method of delivery, the extent of damage to be treated, and other factors. There are many currently ongoing clinical trials for treatment of infarcted heart tissue. Trials of stem cells have expanded to include other common cardiovascular disease modalities including stroke, congestive heart failure, and peripheral artery disease.

Stem Cell Treatment of Type I Diabetes

Type I diabetes is an autoimmune disease caused by destruction of insulin-producing islet β cells in the pancreas. The reduced level of circulating insulin leads to poor control of glucose levels. Whole organ pancreas transplants have been successful; however, there are insufficient numbers of donor pancreases available, and the immunosuppressant therapy required to block host rejection can cause health problems. Injection of pancreatic islet cells had a very low rate of success for many years; although the results are improving, immunosuppressive therapy is still required. Several kinds of stem cell treatments have been attempted for type I diabetes:

Stem cells in the same lineage as islet cells: stem cells have been isolated from both adult pancreas (Banakh et al. 2012) and the biliary tree (intrahepatic and extrahepatic bile ducts). Stem cells in the ducts are thought to be able to differentiate into liver and pancreatic cell types and perhaps contribute to repair and cell turnover in these organs throughout life (Cardinale et al. 2012). Because stem cells from the biliary tree are in the same lineage as pancreatic islet β cells, these may provide a good source of cells for treatment. However, stem cells from the ducts of a patient with diabetes would presumably be subject to immune-mediated destruction once they had differentiated into mature islet cells.

Other stem cells: stem cells from many sources have been used in animal models to at least partially reverse diabetes. Embryonic stem cells (ESCs) can be made to differentiate into pancreatic islets and in some conditions into insulin-secreting structures that resemble islets. Human-derived ESCs have been used to reverse diabetes in mice (Rezania et al. 2014).

A recent study suggests that the immune attack not only destroys islet β cells but also the blood vessels that support the islets (Wan et al. 2013). This suggests that pluripotent stem cells that can differentiate into both islet cells and blood vessel cell types may be required for more effective repair.

Stem cell educator therapy: this is a novel therapy, currently being investigated in a clinical trial (phase 2), that uses cord blood stem cells to educate some of a type I diabetic patient’s own immune cells.

Type I diabetes is a T-cell mediated autoimmune disease. In stem cell educator therapy, a patient’s blood is passed through a blood separator, and the isolated lymphocytes are briefly cocultured with cord blood stem cells. The lymphocytes, but not cord blood cells, are returned to the patient’s body.

It is suggested that a single treatment with stem cell educator can diminish autoimmune attack by T-cells, allowing regeneration of islet β cells and improved glucose control (Zhao 2012, Zhao et al. 2012, 2013).

Encapsulated stem cells: encapsulation allows the cells to secrete insulin into the body, but protects the cells from immune response; immunosuppression is thus not required. This system may also provide a method for the protection of insulin-producing cells derived from autologous stem cells. Clinical trials are underway in New Zealand and Argentina on encapsulated porcine islet cells that are implanted in the abdomen, and the U.S. Food and Drug Administration has approved clinical trials of a human embryonic stem cell–derived therapy for type 1 diabetes, using encapsulated stem cells in a subdermal implant; it is hoped that the cells will mature into stable insulin-producing beta cells (Nature Biotechnology News 2014).

Therapeutic Stem Cell Use in Animals

Veterinary use of stem cells is increasing. Most stem cell transplants in animals are either autologous or adult MSCs from donor animals. Dogs, cats, and horses are the main recipients of stem cells.

Orthopedics including Osteoarthritis

Orthopedics is one area where transplantation of stem cells is currently being used in dogs and horses. The source of stem cells is most commonly adipose-derived MSCs. Osteoarthritis is very common in dogs. Many dogs have been treated for osteoarthritis with stem cells, usually with same-day extraction and transplantation protocols. Outcomes range from substantial improvement to no effect, reflecting both the diversity of underlying causes and the different stem cell preparation protocols.

Other orthopedic uses of stem cells in animals include repairing tendon, ligament, and muscle tears, and bone regeneration. Stem cells are also being investigated for use in heart disease and spinal cord injuries. There are now several companies that provide kits and equipment for the removal and processing of stem cells from animals. Animal stem cell banking is also available; stem cells are harvested during neutering, spaying, or other procedures requiring anesthesia and stored for future use, so stem cells from one collection can be used for multiple treatments.

Stem Cell Banking for Endangered Animal Conservation

Banking of stem cells is being investigated as a means for protecting endangered animals. The aim is to keep genetic diversity as high as possible. If an endangered animal dies before breeding, then diversity is lost from the pool. The goal would be to preserve viable stem cells until techniques such as somatic transplantation become more reliable.

Tissue Engineering

A major therapeutic goal of stem cells is whole or partial organ replacement by growing the replacement tissue prior to implanting in a patient. This is a challenging undertaking; not only must the engineered tissue form the correct 3-D structure, but the multiple cell types must be correctly located relative to each other and those of the recipient.

Stem cells provide several advantages for tissue engineering. For example, autologous stem cells can be harvested from a different area of the body than where treatment is required. Additionally, pluripotent stem cells can be differentiated into any cell type, potentially providing all the cell types needed for fully functional tissue.

A scaffold is required: one of the first steps in tissue engineering is the generation of a suitable scaffold so that the tissue assumes the correct shape. For tissues that are relatively two dimensional and simple, inkjet technology has been one way to introduce multiple cell types onto a scaffold. Recently, 3-D printing has been tested as a method to generate tissue scaffolds. This method has several potential advantages over other techniques including the ability to make fully 3-D structures and place different types of cells precisely within the structure.

Trachea was the first tissue to be implanted: artificial trachea transplants are one example with several successful implantations of engineered tissue; a scaffold is incubated in a bioreactor with stem cells from the patient and then implanted (Macchiarini et al. 2008, Elliott et al. 2012).

Mobilization and engraftment of local stem cells: a parallel area of research is the stimulation, mobilization, and engraftment of local stem cells as an alternative to transplantation. This type of treatment is particularly suited to repair after injury. The aim is to find treatments that stimulate stem cells in the area of the wound to migrate, proliferate, differentiate, and repair tissue. An advantage of this method is that local signals may promote appropriate outgrowth and proper placement of blood vessels, neurons, and connective tissue.

An example of this kind of repair is the treatment of a soldier wounded in Afghanistan who lost part of his quadricep muscle in one leg. The skin healed, but the muscle was only marginally functional. A sheet of decellularized extracellular matrix from a pig urinary bladder was implanted in the thigh, as animal extracellular matrix can serve as scaffolding and stimulate stem cells. Local recruitment of stem cells that differentiated into muscle cells increased the tissue volume and restored much of the lost function of the quadriceps (Sicari et al. 2014).

Stem Cells as Models for Basic Research and Disease and Drug Testing

Animals May or May Not Be Good Model Systems

Studying disease, development, and cell and tissue function has relied mainly on animal models, usually rodents. Animal models have provided a lot of valuable information, but vary in the degree to which they resemble humans. Some aspects of the physiology of model animals are different from their human counterparts, and for a number of diseases, there are no animal models that directly mirror the human disease.

Problems with Most Current (Nonstem) Cell Lines

The majority of cultured cell lines are functionally and often morphologically different from the cell type from which they were derived. Not only have most human and animal cell lines been transformed in some way to permit them to be maintained in culture, but cells change as they are maintained in culture in response to culturing conditions. Readily available sources of stem cells will provide models that are closer to the native phenotype and genotype.

Induced Pluripotent Stem Cells (iPSCs) as Models

The first widespread use of stem cells as a model was with iPSCs. The ability to make iPSCs from tissues such as skin has made them a widespread and uncontroversial model system. Somatic (adult) stem cells can be reprogrammed to become iPSCs by forced expression of stem cell transcription factors such as Oct3/4.

One consideration for using iPSCs as model cells is that epigenetic memory has been observed in iPSCs. The pattern of DNA methylation changes during development, and some of this methylation pattern remains during reprogramming. This suggests that multiple iPSC models from somatic cells from different lineages should be compared to see where epigenetic bias affects results, or that iPSCs should be generated from the same lineage as the lineage that is going to be modeled.

Somatic Cell Nuclear Transfer (SCNT) to Generate Cell Lines

SCNT is the transfer of an isolated somatic (adult) nucleus into an enucleated egg. The somatic nucleus is reprogrammed by the egg. Then the egg is stimulated to divide, usually by an electric shock. For cloning an entire organism, such as Dolly the sheep (Wilmut et al. 1997), after a number of cell divisions, the embryo is implanted into a surrogate mother.

hESC lines were recently generated using nuclei from skin fibroblasts (Tachibana et al. 2013). The goal was not to clone humans but to develop an efficient method with fewer ethical issues for the creation of custom human stem cell lines. It remains to be determined whether SCNT reverses the development-associated DNA methylation of the somatic cell or whether, as with iPSCs, some of the somatic cell epigenetic memory remains.

Stem Cell Models in Basic Research

The pool of potential stem cell models is increasing rapidly. Methods for reprogramming different somatic cells and for differentiation to obtain different phenotypes are actively expanding areas of research.

Although much of the initial focus has been on stem cell models for disease, stem cells provide tractable models for the study of all aspects of cell biology. Stem cell models are being used to study many cell functions in both stem cells and stem cell-derived somatic cell lines including:

  • Mechanisms and signals for stem cell proliferation (symmetric and asymmetric)
  • Signals that trigger migration
  • Signals and pathways involved in differentiation
  • Pathways for differentiation to different phenotypes
  • Sequences of epigenetic changes during differentiation into different lineages and cell types
  • Cell functions of stem and somatic cells under normal, nonstressed conditions
  • Changes in cell functions under stress
  • Changes in cell functions upon stimulation
  • Apoptosis
  • Cell death
  • Functions and behaviors of stem cells
  • Roles of stem cells in normal development, growth, and repair

High-throughput gene targeting: ESCs from mice are a genetically tractable model to study both basic cell biological and developmental processes on a genome-wide scale. The International Mouse Phenotyping Consortium is in the process of mutating all protein-coding genes in the mouse genome. Mouse C75BL/6N ESCs with reporter-tagged mutations are being generated by gene trapping and gene targeting. These ESC lines are available for researchers as they are developed.

Chimeras: mouse chimeras have provided a lot of information about cell development and lineages. A common method is to inject ESCs into the cavity of a blastocyst. Generally, ESCs are tagged so that daughter cells can be tracked. To study the effects of changes in gene expression, prior to injection, ESCs are subjected to homologous recombination to either knock out or knock in a gene. Chimeras are being used to investigate early cell fate, cell and tissue development, cell functions, and diseases.

Stem Cell Models for Disease

The generation of stem cell models from somatic cells provides the ability to develop stem cell lines for many diseases including those with adult onset. Comparison of normal and disease stem cells will:

  • Identify disease phenotype(s)
  • Investigate the development of the disease phenotype
  • Profile control and disease cells at transcriptome and protein levels to reveal differences
  • Measure functional changes
  • Determine which cell types are affected by the disease
  • Identify disease biomarkers and potential new diagnostics

Biomarker discovery: one goal in research on any disease is the discovery of biomarkers. The identification of biomarkers provides a way to track diseases and, for some biomarkers, the development of tests. If biomarkers are expressed early in the disease, sensitive detection may permit diagnosis and treatment at early stages, before there is significant damage or complications.

New cell models: stem cell models are being used for many cell types that were previously hard to model. For example, cells of the human nervous system such as dopaminergic neurons have been hard to study due to the difficulty of obtaining living cells. The progressive death of dopaminergic neurons results in Parkinson’s disease. Studies of neurons generated from iPSCs derived from Parkinson’s patients are now being used to elucidate the mechanisms and the course of disease progression at a fine cellular level.

Comparative analysis: using stem cell models from different animals provides complementary information. For instance, what are the differences in stem cells, cell differentiation, and cell dedifferentiation between animals that can easily regenerate an organ and those that have minimal regenerative capacity? Could this type of information contribute to a better understanding of regeneration and wound repair?

Drug Discovery and Testing with Stem Cells

The ability to generate large populations of cells with defined phenotypes is having an impact on drug discovery and testing. Stem cell–derived model systems can be used for all aspects of drug discovery and early testing, including:

  • Screening compounds for changes in known biomarkers
  • Screening compounds or pools of compounds for changes in disease phenotype
  • Evaluating the mechanism(s) of alteration of disease by lead compounds
  • Toxicity screening
  • Screening different cell lines to ensure applicability to a whole population rather than small subpopulations
  • Safety and effects in nontarget cell types
  • In vitro clinical trials
  • Reduced animal testing (and associated costs)


The use of stem cells in research and clinical settings is increasing rapidly. As new ways are identified to generate and manipulate stem cells, they will become integral to research in cell biology and disease as well as useful in the treatment of many diseases.


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