HEMATOLOGY EBOOK

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 tissues. Also known as somatic stem cells (from Greek Σωματικóς, meaning of the body), they can be found in juvenile as well as adult animals and humans.

Scientific interest in adult stem cells has centered on their ability to divide or self-renew indefinitely, and generate all the cell types of the organ from which they originate, potentially regenerating the entire organ from a few cells. Unlike embryonic stem cells, the use of adult stem cells in research and therapy is not considered to be controversial as they are derived from adult tissue samples rather than destroyed human embryos. They have mainly been studied in humans and model organisms such as mice and rats.

 

Stem cell division and same. A – stem cells; B – progenitor cell; C – differentiated cell; 1 – symmetric stem cell division; 2 – asymmetric stem cell division; 3 – progenitor division; 4 – terminal differentiation

Properties

Defining properties

The rigorous definition of a stem cell requuires that it processes two properties:

• Self-renewal which is the ability to go through numerous cycles of cell division while maintaining the undifferentiated state.
• multipotency or multidifferentiative potential which is the ability to generate progeny of several distinct cell typer, (for example glial cells are restricted to producing a single-cell type. However, some researchers do not consider multipotency to be essential, and believe that unipotent self-renewing stem cells can exist.

These properties can be illustrated with relative ease in vitro, using methods such as clonogenic assays, where the progeny of a single cell is characterized, however, it is known that in vitro cell culture conditions can alter the behavior of cells. Proving that a particular subpopilation of cells possesses stem cell properties in vivo is challenging, and so considerable debate exists as to whether some proposed stem cell populations in the adult are indeed stem cells.

Lineage

To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter cells, both endowed with stem cell properties, whereas assymmetric division produces only one stem cell and a progenitor cell with limited self-renewal potential. Asymmetric division is the process of a cell splitting into another cell and en essential cell fat, or a lipid, this lipid will bond to a free cell and reproduce. Progenitors can go through several rounds of cell division before finally differentiating into a mature cell. It is believed that the molecular distinction between symmetric and asymmetric divisions lies in differential segragation of cell membrane proteins (such as receptors) between the daughter cells.

Multidrug resistance

Adult stem cells express transporters of the ATP-binding cassette family that actively pump a diversity of organic molecules out of the cell. Many pharmaceuticals are exported by these transportrs conferring multidrug resistance onto the cell. This complicates the design of drugs, for instance neural stem cell targeted therapies for the treatment of clinical depression.

Signaling pathways

Adult stem cell research has ben focused on uncovering the general molecular mechanisms that control their self-renewal and differentiation.

Bmi-1

The transcriptional repressor Bmi-1 is one of the Polycomb-group proteins that was discovered as a common oncogene. activated in lymphoma and later shown to specifically regulate HSCs. The role of Bmi-1 has also been illustrated in neural stem cells.

Notch

The Notch pathway has been known to devlopmental biologists for decades. Its role in control of stem cell proliferation has now been demonstrated for several cell types including haematopoietic, neural and mammary stem cells.

Wnt

These developmental pathways are also strongly implicated as stem cell regulators.

 Plasticity

Under special conditions tissue-specific adult stem cells can generate a whole spectrum of cell-types of other tissues, even crossing germ layers. This phenomenon is referred to as stem cell transdifferentiation or plasticity. It can be inducd by modifying the growth medium when stem cells are cultured in vitro or tranplanting them to an organ of the body different from the one they were originally isolated from. There is yet no consensus among biologists on the prevlalence and physiological and therapeutic relevance of stem cell plasticity.

Types

Hematopoietic stem cells

Hematopoietic stem cells are found in the bone marrow and give to the blood cell types.

Mammary stem cells

Mammary stem cells provide the source of cells for growth of the mammary gland during puberty and gestation and play an important role in carcinogenesis of the breast. Mammary stem cells have been isolated from human and mouse tissue as well as from cell lines derived from the mammary gland. Single such cells can give rise to both the luminal and myoepithelial cell types of the gland, and have been shown to have the ability to regenerate the entire organ in mice.

Mesenchymal stem cells

Mesenchymal stem cells (MSCs) are of stromal origin and may differentiate into a variety of tissues. MSCs have been isolated from placenta, adipose tissue, lung, bone marrow and blood, Wharton’s jelly from the umbilical cord, and teeth (perivascular niche of dental pulp and periodontal ligament). MSCs are attractive for clinical therapy due to their ability to differentiate, provide trophic support, and modulate innate immune response.

Endothelial stem cell

Endothelial stem cells are multipotent stem cells. They are one of three types of stem cells to be found in bone marrow.

Neural stem cells

The existence of stem cells in the adult brain has been prostulated following the discovery that the process of neurogenesis, the birth of new neurons, continues into adulthood in rats. The presence of stem cells in the mature primate brain was first reported in 1967. It has since been shown that new neurons are generated in adult mice, songbirds and primates, including humans. Normally, adult neurogenesis is restricted to two areas of the brain – the subventricular zone, which lines the lateral ventricles, and the dentate gyrus of the hippocampal formation. Although the generation of new neurons in the hippocampus is well established, the presence of tue self-renewing stem cells there has been debated. Under certain circumstances, such as following tissue damage is ischemis, neurogenesis can be induced in other brain regions including the neocortex.

Neural stem cells are commonly cultured in vitro as so called neuropheres – floating heterogeneous aggregates of cells, containing a large proportion of stem cells. They can be propagated for extended periods of time and differentiated into both neuronal and glia cells, and therefore behave as stem cells. However, some recent studies suggest that this behaviour is induced by the culture onditions in progenitor cells, the progeny of stem cell division that normally undergo a strictly limited number of replication ccles in vivo. Furthermore, neurosphere-derived cells do not behave as stem cells when transplanted back into the brain.

Neural stem cells share many properties with haematopoietic stem cells (HSCs). Remarkably, when injected into the blood, neurosphere-derived cells differentiate into various cell types of the immune system.

Olfactory adult stem cells

Olfactory adult stem cells have been successfully hrvested from the human olfactory mucosa cells, which are found in the lining of the nose and are involved in the sense of smell. If they are given the right chemical environment these cells have the same ability as embryonic stem cells to develop into many different cell types. Olfactory stem cells hold the potential for therapeutic applications and, in contrast to neural stem cells, can be harvested with ease without harm to the patient. This means they can be easily obtained from all individuals, including older patients who might be most in need of stem cell therapies

Neural crest stem cells

Hair follocles contain two types of stem cells, one of which appears to represent a remnant of the stem cells of the embryonic neural crest. Similar cells have been found in the gastrointestinal tract, sciatic nerve, cardiac outflow tract and spinal and sympathetic ganglia. These cells can generate neurons, Schwann cells, myofibroblast, chondocytes and melanocytes.

Testicular cells

Multipotent stem cells with a claimed equivalency to embryonic stem cells have been derived from spermatogonial progenitor cells found in the testicles of laboratory mice by scientists in Germany and the United Kingdom confirmed the same capability using celss from the testicles og humans. The extracted stem cells are known as human adult germline stem cells.

Multipotent stem cells have also been derived from germ cells found in human testicles.

Adut stem cell therapies

The therapeutic potential of adult stem cells is the focus of much scientific research, due to their ability to be harvested from the patient . In common with embryonic stem cells, adult stem cells have the ability to differentiate into more than one cell type, but unlike the former they are often restricted to certain types or “lineages”. The ability of a differentiated stem cell of one lineage to ptoduce cells of a different lineage is called transdifferentiation. Some types of adult stem cells are more capable of transdifferentiation than others, and for many there is no evidence that such a transformaation is possible. Consequently, adult stem therapies require a stem cell source of the specific lineage needed, and harvesting and/or culturing them up to the numbers required is a challenge.

Sources

Pluripotent stem cells, i.e. cells that can give rise to any fetal or adult cell tupe, can be found in a number of tissues, including umbilical cord blood. Using genetic reprogramming, pluripotent stem cells equivalent to embronic stem cells have been derived from human adult skin tissue. Other adult stem cells are multipotent, meaning they are restricted in the types of cell they can become, and are generally referred to by their tissue origin (such as mesenchymal stem cell, adipose-derived stem cell, endothelial stem cell, etc). A great deal of adult stem cell research has focused on investigating their capacity to divide or self-renew indefinitely, and their potential for differentiation. In mice, pluripotent stem cells can be directly generated from adult fibroblast cultures.

Cllinical Applications

Adult stem cell treatments have been used for many years to successfully treat leukemia and related bone/blood cancers utilizing bone marrow transplants. The use of adult stem cells in research and therapy is not considered as controversial as the use of embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo. Consequently, the majority of US government funding provided for research in this field is restricted to supporting adult stem cell research.

Early regenerative applications of adult stem cells has focused on intravenous delivery of blood progenitors known as Hematopetic Stem Cells (HSC’s). Other early commercial applications have focused on Mesenchymal Stem Cells (MSC’s). For both cell lines, direct injection or placement of cells into a site in need of repair may be the preferred method of treatment, as vascular delivery suffers from a “pulmonary first pass effect” where intravenous injected cells are sequestered in the lungs. Clinical case reports in orthopedic applications have been published. Wakitani has 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.Centeno et al. have reported high field MRI evidence of increased cartilage and meniscus volume in individual human clinical subjects. Many other stem cell based treatments are operating outside the US, with much controversy being reported regarding these treatments as some feel more regulation is needed as clinics tend to exaggerate claims of success and minimize or omit risks.

First transplanted human organ grown from adult stem cells

 In 2008 the first full transplant of a human organ grown from adult stem cells was carried out by Paolo Macchiarini, at the Hospital Clínic of Barcelona on Claudia Castillo, a Colombian female adult whose trachea had collapsed due to tuberculosis. Researchers from the University of Padua, the University of Bristol, and Politecnico di Milano harvested a section of trachea from a donor and stripped off the cells that could cause an immune reaction, leaving a grey trunk of cartilage. This section of trachea was then “seeded” with stem cells taken from Ms. Castillo’s bone marrow and a new section of trachea was grown in the laboratory over four days. The new section of trachea was then transplanted into the left main bronchus of the patient. Because the stem cells were harvested from the patient’s own bone marrow Professor Macchiarini did not think it was necessary for her to be given anti-rejection (immunosuppressive) medication and when the procedure was reported four months later in The Lancet, the patient’s immune system was showing no signs of rejecting the transplant

Adult stem cells and cancer

In recent years, acceptance of the concept of adult stem cells has increased. There is now a theory that stem cells reside in many adult tissues and that these unique reservoirs of cells are not only responsible for the normal reparative and regenerative processes, but are also considered to be a prime target for genetic and epigenetic changes, culminating in many abnormal conditions including cancer