Читать книгу The SAGE Encyclopedia of Stem Cell Research - Группа авторов - Страница 68

About 65 years ago, a team of researchers discovered that red bone marrow was composed of two types of stem cells: hematopoietic stem cells (HSCs) described as mesoderm-derived blood cells, and stromal stem cells. Cells of the mesoderm form one of the three primary germ cell layers of an embryo in its early stages of development, and give rise to other blood cells. Stromal stem cells, on the other hand, constitute the so-called skeletal or mesenchymal layer. The role of these stem cells, which only make up a fraction of all stromal cells, is to generate cartilage, bone, and fat cells able to support the formation of fibrous connective tissue and blood.

Despite these findings, most scientists remained convinced for a long time that the adult human brain was unable to produce new nerve cells. In the 1990s, however, researchers reached the conclusion that the matured brain did contain stem cells, capable of generating star-shaped glial cells called astrocytes, located in the spinal cord and the brain, and oligodendrocytes, which provide insulation and support to axons, long nerve fiber extensions present in the central nervous system (CNS) of some vertebrates.

While hematopoietic stem cells only produce white blood cells, red blood cells, and platelets, adult stem cells, in contrast, mutate into different kinds of cells susceptible of dividing and reproducing indefinitely.

What are adult stem cells (ASCs) all about? And more specifically, how do they differ from pluripotent stem cells, or rapidly dividing progenitor transit amplifying cells (TACs)? Why are they so important to science and regenerative medicine? What are the challenges, if any, associated to their use?

By definition, “adult stem cells are undifferentiated cells, found throughout the body after embryonic development, that multiply by cell division to replenish dying cells and regenerate damaged tissue.” They are also known as somatic stem cells, found in young and adult animals, and humans.

Many different types of stem cells arise at different locations in the human body, from adult or tissue-specific stem cells, to embryonic stem cells that exist only briefly in the early stages of tissue development. In addition to these, researchers have recently created induced pluripotent stem cells, or iPSCs. These are undifferentiated cells engineered from specialized cells, with characteristics almost identical to those of embryonic stem cells.

Adult or tissue-specific stem cells are deemed to be multipotent, that is, capable of giving rise to a few mature cell types.

Adult stem cells are present in many different tissues and organs, including brain, blood, vessels, skin, skeletal muscle, heart, testis, ovarian epithelium, and bone marrow. In the bone marrow, several millions of new blood cells arise every day from blood-forming stem cells. Scientists have not been able to determine whether every mature organ includes stem cells. Tissue-specific stem cells are rare and often difficult to grow in culture and isolate. Of those, the blood-forming and hematopoietic stem cells residing in the bone marrow are the most studied.

Induced pluripotent stem cells (iPSCs) are cells engineered to become pluripotent, that is, capable of forming multiple types of cell types. Although human iPSCs open up an exciting window into stem cell research, this technology is still in its infancy, and many related crucial questions remain unanswered.

A promising avenue of stem cell research resides in the replacement of affected or damaged cells with healthy ones, an approach defined as regenerative medicine. This field has prompted scientists to investigate the use of fetal, embryonic, and adult stem cells derived from various specialized cell types—muscle, nerve, blood, and skin cells—to assess their use as potential treatment for various conditions.

However, it is important to keep in mind that in some instances, the immune system itself may be the source of so-called autoimmune diseases that damage vital cells, such as the ones producing insulin in type 1 diabetes patients.

The end goal of stem cell–based regenerative medicine—the restoration of the function of damaged or lost tissues and organs—can be achieved through different means such as the injection of stem cells engineered in the laboratory, or the administration of drugs susceptible of coaxing existing stem cells into carrying out a more efficient repair.

However, in spite of the encouraging prospects presented by potential stem cell therapies, there are challenges in the use of stem cells for regenerative purposes. In adult individuals, tissue-specific stem cells are rare and tend to be difficult to isolate. Additionally, while adult stem cells hold the promise of self-regeneration in animals and humans, the fact that they only exist in minute quantities creates some hurdles in the sense that they must be identified in sufficient numbers in order to be usable for therapy. All this makes it harder to conduct effective clinical studies. Researchers from various laboratories are currently attempting to find ways to grow and collect large enough quantities of adult stem cells susceptible to generate specific cell types.

Blood-forming stem cells make up only a tiny fraction of the bone marrow. Although, they can be isolated in the laboratory, these cells cannot be conserved for a long time. Some cells, such as skin stem cells, offer better expansion capabilities in the laboratory and are used for specific treatments like burns. Other types of stem cells, such as bone marrow cells, can be infused in the blood stream. Mesenchymal muscle and neural stem cells, on the other hand, present more challenging routes for administration. Another obstacle is the potential rejection by the immune system of stem cells originating from donors other than the patient. This sometimes leads to the need to harvest stem cells from the intended recipient of the related therapy.

Finally, an added drawback of adult stem cells is their relative age compared to embryonic stem cells, which makes them more susceptible to DNA abnormalities caused by toxins, random errors, or environmental factors.

All embryonic stem cells arise from young embryos and are usually genetically different from those of any potential recipient. They can therefore be rejected by the immune system, the reason why iPSCs collected from the patient’s cells through reprogramming constitutes such a major breakthrough.

A major advantage of pluripotent cells is that they can be grown and expanded indefinitely in the laboratory. Therefore, in contrast to adult stem cells, sheer quantity will be less of a limiting factor. Another advantage of these cells is the large number of different cell types present in a given organ that they can generate. This enables the development of a multitude of tissue-engineering approaches aimed at reconstructing a variety of organs in the lab.

Scientists are using many different methods of identification of adult stem cells. One of them is their labeling within a living tissue by means of molecular markers enabling the determination of the types of specialized cell they are susceptible to generate. Another procedure involves the extraction of cells from a living animal, their labeling in cell culture, and their transplantation into another animal to see whether these cells are restored inside their original tissue.

One of the major tasks confronting researchers is to demonstrate that a single adult stem cell is able to produce a series of genetically identical cells which, in turn, would give rise to differentiated cell types.

What do we currently know about stem cell differentiation? What are the pathways leading to such a process?

In living animals, and as needed, adult stem cells have the ability to divide and give rise to mature cell types that feature the functions, shapes, and specialized structures of a given tissue.

For instance, hematopoietic stem cells (HSCs) are known to produce all kinds of blood cells, including B or T lymphocytes, natural killer or red blood cells, basophils, neutrophils, eosinophils, macrophages, and monocytes.

On the other hand, neural stem cells located in the brain generate three major cell types: oligodendrocytes, astrocytes, and nerve cells, while skin stem cells that line up the base of hair follicles and the basal layer of the epidermis give rise to keratinocytes. In the lining of the digestive tract, epithelial stem cells are embedded in crypts and produce goblet, absorptive, entero-endocrine, and paneth cells.

Mesenchymal stem cells (MSCs)—multipotent skeletal stem cells, or stromal cells susceptible to differentiate into a variety of cell types—can give rise to a certain number of cell types, including bone cells (osteocytes and osteoblasts), fat cells (adipocytes), cartilage cells (chondrocytes), and stromal cells that are in support of blood formation.

Transdifferentiation is generally defined as “lineage reprogramming,” a process during which a mature somatic cell transmutes into another without going through an intermediate pluripotent state. The adult stem cell types involved may then differentiate into other types of cells located in tissues or organs, differing from those expected to derive from the original cells’ anticipated pedigree. One such example is blood-forming cells, capable of differentiating into cardiac muscle cells.

Isolated occurrences of transdifferentiation have been witnessed in some vertebrates, but, according to the scientific community, none has yet been observed in humans. In cases where certain adult stem cells could be “reprogrammed” into other types of cells, such capability provides a way to repair damaged cell types in the aftermath of a disease. It has been proven quite recently through experimentation that insulin-producing cells damaged or lost due to diabetes can possibly regain functionality through the reprogramming of other pancreatic cells.

In addition to “lineage reprogramming,” adult somatic cells can be reengineered to behave like embryonic stem cells (ESCs) through the insertion of pluripotency genes.

For many years now, research on adult stem cells has triggered a great deal of interest and excitement among the community of scientists and clinicians. This is certainly due to the capacity these cells demonstrate to self-renew indefinitely, thus constituting a renewable source of tissue and cell replacement in the treatment of a series of diseases, and the potential regeneration of entire organs from a few cells.

For over 40 years, bone marrow transplants based on the use of adult stem cells have made it possible to successfully treat cancers such as lymphomas, myelomas, and leukemia and genetic diseases such as thalassemias. This progress has opened new doors to regenerative therapy and has led to a surge in clinical trials relying on the use of adult stem cells. These developments are providing great hope for the treatment of conditions such as diabetes, myocardial infarction, congestive heart failure, and so forth.

A new trend in the field of stem cell biology is the adoption of all-inclusive concepts illustrated by the definition of a flurry of new scientific terms. Notwithstanding this tendency, recent studies suggest that functional differences do exist between stem and so-called progenitor cells.

Stem cells are called progenitors when they do not have the capacity to self-renew. In the past, developmental biologists referred to ancestral embryonic cells as precursors. For any particular cell in the embryo, there exists an ancestor (progenitor or precursor) cell that gives rise to it. The notion of transit-amplifying cells (TAC) also needs to be clarified in this constantly shifting biological landscape. The difference between TACs and progenitors is not always clear.

Transit-amplifying cells might be defined as dedicated progenitors among adult stem cells. Progenitor cells are known to have potential uses in medicine. Researchers from the Boston Children’s Hospital are currently reviewing the potential of muscle and blood progenitor cells in building blood vessels and heart valves, for instance.

Adult stem cells are located in a specific microenvironment known as a niche, in which both adult stem cells and TAC stay under control during their differentiation and self-renewing processes. If the differentiation of adult stem cells can be monitored in a laboratory environment, such cells may serve as a basis of transplantation-based therapies, especially since, unlike embryonic stem cells, the use of human adult stem cells in research is not considered controversial: the cells are extracted from adult tissue samples rather than young human embryos bound to have been destroyed.

It is true that adult stem cells do not carry the same ethical concerns, or generate the same level of controversy, as embryonic stem cells. However, the practical challenges involved in their use are real. As scientists continue to explore ways to successfully harvest adult stem cells, the public awaits new therapies for some of the more severe afflictions. Looking at the potential clinical applications of stem cells, scientists have reached the conclusion that stem cell treatments have the potential to make great impact on the general well-being of populations and individuals, physically, psychologically, and economically.

Approximately 130 million people suffer today from some kind of degenerative, chronic disease. In this context, stem cell therapies hold great promise, in particular in the treatment of many conditions affecting the nervous system that usually result from a loss of nerve cells. However, because mature nerve cells cannot divide, they cannot be relied on to replace lost cells. These types of conditions do not offer any therapeutic options outside of the regeneration of damaged or lost nerve tissue. This is true of Parkinson’s disease, in which nerve cells secreting dopamine die; Alzheimer’s disease cells, in which neurotransmitters are depleted; or amyotrophic sclerosis; in which motor nerve cells responsible to activate muscles are destroyed.

In primary immunodeficiency diseases such as AIDS, adult stem cells offer the promise of treating such conditions through stem cell therapy. Pluripotent stem cells, the master cells capable of generating cells from the three basic body layers, such as adult stem cells, can self-renew. In so doing, they are able to regenerate the missing immune cells at the basis of nearly all primary immunodeficiency illnesses. The transplantation of reconstituted stem cells using normal genes could therefore restore the immune function and provide a new quality of life to affected individuals.

What are the challenges to the use of adult stem cells?

For many years, adult stem cells have been used therapeutically in the form of bone marrow transplants. Nevertheless, the scientific community is still facing today a series of challenges that need to be overcome before stem cells can be deemed ready to effectively treat a wider range of diseases.

Researchers are still attempting to grasp the unique molecular and genetic basis for the phenomenon enabling these cells to replicate endlessly. As we can see, challenges pertaining to the immune system constitute a significant impediment to the reliable application of stem cell therapies.

Cell therapy surely provides exceptional prospects to disease treatment, yet the value of these technological accomplishments will only be fully realized once the therapeutic techniques underway are carefully applied to patients through clinical programs capable of ensuring efficacious and tangible results at a reasonable cost.

Morenike Trenou

Independent Scholar

See Also: Embryonic Stem Cells, Methods to Produce; Pluripotent Stem Cells, Embryonic; Pluripotent Stem Cells, Germ; Stem Cell Markers.