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It is often difficult—if not impossible—to distinguish adult, tissue-specific stem cells from progenitor cells. With that caveat in mind, the following summary identifies reports of stem cells in various adult tissues.
Endothelial Progenitor Cells. Endothelial cells line the inner surfaces of blood vessels throughout the body, and it has been difficult to identify specific endothelial stem cells in either the embryonic or the adult mammal. During embryonic development, just after gastrulation, a kind of cell called the hemangioblast, which is derived from mesoderm, is presumed to be the precursor of both the hematopoietic and endothelial cell lineages. The embryonic vasculature formed at this stage is transient and consists of blood islands in the yolk sac. But hemangioblasts, per se, have not been isolated from the embryo and their existence remains in question. The process of forming new blood vessels in the embryo is called vasculogenesis. In the adult, the process of forming blood vessels from pre-existing blood vessels is called angiogenesis [50].
Evidence that hemangioblasts do exist comes from studies of mouse embryonic stem cells that are directed to differentiate in vitro. These studies have shown that a precursor cell derived from mouse ES cells that express Flk-1 [the receptor for vascular endothelial growth factor (VEGF) in mice] can give rise to both blood cells and blood vessel cells [88, 109]. Both VEGF and fibroblast growth factor-2 (FGF-2) play critical roles in endothelial cell differentiation in vivo [79].
Several recent reports indicate that the bone marrow contains cells that can give rise to new blood vessels in tissues that are ischemic (damaged due to the deprivation of blood and oxygen) [8, 29, 49, 94]. But it is unclear from these studies what cell type(s) in the bone marrow induced angiogenesis. In a study which sought to address that question, researchers found that adult human bone marrow contains cells that resemble embryonic hemangioblasts, and may therefore be called endothelial stem cells.
In more recent experiments, human bone marrow-derived cells were injected into the tail veins of rats with induced cardiac ischemia. The human cells migrated to the rat heart where they generated new blood vessels in the infarcted muscle (a process akin to vasculogenesis), and also induced angiogenesis. The candidate endothelial stem cells are CD34+(a marker for HSCs), and they express the transcription factor GATA-2 [51]. A similar study using transgenic mice that express the gene for enhanced green fluorescent protein (which allows the cells to be tracked), showed that bone-marrow-derived cells could repopulate an area of infarcted heart muscle in mice, and generate not only blood vessels, but also cardiomyocytes that integrated into the host tissue [71] (see Chapter 9. Can Stem Cells Repair a Damaged Heart?).
And, in a series of experiments in adult mammals, progenitor endothelial cells were isolated from peripheral blood (of mice and humans) by using antibodies against CD34 and Flk-1, the receptor for VEGF. The cells were mononuclear blood cells (meaning they have a nucleus) and are referred to as MBCD34+ cells and MBFlk1+ cells. When plated in tissue-culture dishes, the cells attached to the substrate, became spindle-shaped, and formed tube-like structures that resemble blood vessels. When transplanted into mice of the same species (autologous transplants) with induced ischemia in one limb, the MBCD34+ cells promoted the formation of new blood vessels [8]. Although the adult MBCD34+ and MBFlk1+ cells function in some ways like stem cells, they are usually regarded as progenitor cells.
Skeletal Muscle Stem Cells. Skeletal muscle, like the cardiac muscle of the heart and the smooth muscle in the walls of blood vessels, the digestive system, and the respiratory system, is derived from embryonic mesoderm. To date, at least three populations of skeletal muscle stem cells have been identified: satellite cells, cells in the wall of the dorsal aorta, and so-called "side population" cells.
Satellite cells in skeletal muscle were identified 40 years ago in frogs by electron microscopy [62], and thereafter in mammals [84]. Satellite cells occur on the surface of the basal lamina of a mature muscle cell, or myofiber. In adult mammals, satellite cells mediate muscle growth [85]. Although satellite cells are normally non-dividing, they can be triggered to proliferate as a result of injury, or weight-bearing exercise. Under either of these circumstances, muscle satellite cells give rise to myogenic precursor cells, which then differentiate into the myofibrils that typify skeletal muscle. A group of transcription factors called myogenic regulatory factors (MRFs) play important roles in these differentiation events. The so-called primary MRFs, MyoD and Myf5, help regulate myoblast formation during embryogenesis. The secondary MRFs, myogenin and MRF4, regulate the terminal differentiation of myofibrils [86].
With regard to satellite cells, scientists have been addressing two questions. Are skeletal muscle satellite cells true adult stem cells or are they instead precursor cells? Are satellite cells the only cell type that can regenerate skeletal muscle. For example, a recent report indicates that muscle stem cells may also occur in the dorsal aorta of mouse embryos, and constitute a cell type that gives rise both to muscle satellite cells and endothelial cells. Whether the dorsal aorta cells meet the criteria of a self-renewing muscle stem cell is a matter of debate [21].
Another report indicates that a different kind of stem cell, called an SP cell, can also regenerate skeletal muscle may be present in muscle and bone marrow. SP stands for a side population of cells that can be separated by fluorescence-activated cell sorting analysis. Intravenously injecting these muscle-derived stem cells restored the expression of dystrophin in mdx mice. Dystrophin is the protein that is defective in people with Duchenne's muscular dystrophy; mdx mice provide a model for the human disease. Dystrophin expression in the SP cell-treated mice was lower than would be needed for clinical benefit. Injection of bone marrow- or muscle-derived SP cells into the dystrophic muscle of the mice yielded equivocal results that the transplanted cells had integrated into the host tissue. The authors conclude that a similar population of SP stem cells can be derived from either adult mouse bone marrow or skeletal muscle, and suggest "there may be some direct relationship between bone marrow-derived stem cells and other tissue- or organ-specific cells" [43]. Thus, stem cell or progenitor cell types from various mesodermally-derived tissues may be able to generate skeletal muscle.
Epithelial Cell Precursors in the Skin and Digestive System. Epithelial cells, which constitute 60 percent of the differentiated cells in the body are responsible for covering the internal and external surfaces of the body, including the lining of vessels and other cavities. The epithelial cells in skin and the digestive tract are replaced constantly. Other epithelial cell populations—in the ducts of the liver or pancreas, for example—turn over more slowly. The cell population that renews the epithelium of the small intestine occurs in the intestinal crypts, deep invaginations in the lining of the gut. The crypt cells are often regarded as stem cells; one of them can give rise to an organized cluster of cells called a structural-proliferative unit [93].
The skin of mammals contains at least three populations of epithelial cells: epidermal cells, hair follicle cells, and glandular epithelial cells, such as those that make up the sweat glands. The replacement patterns for epithelial cells in these three compartments differ, and in all the compartments, a stem cell population has been postulated. For example, stem cells in the bulge region of the hair follicle appear to give rise to multiple cell types. Their progeny can migrate down to the base of the follicle where they become matrix cells, which may then give rise to different cell types in the hair follicle, of which there are seven [39]. The bulge stem cells of the follicle may also give rise to the epidermis of the skin [95].
Another population of stem cells in skin occurs in the basal layer of the epidermis. These stem cells proliferate in the basal region, and then differentiate as they move toward the outer surface of the skin. The keratinocytes in the outermost layer lack nuclei and act as a protective barrier. A dividing skin stem cell can divide asymmetrically to produce two kinds of daughter cells. One is another self-renewing stem cell. The second kind of daughter cell is an intermediate precursor cell which is then committed to replicate a few times before differentiating into keratinocytes. Self-renewing stem cells can be distinguished from this intermediate precusor cell by their higher level of β1 integrin expression, which signals keratinocytes to proliferate via a mitogen-activated protein (MAP) kinase [112]. Other signaling pathways include that triggered by -catenin, which helps maintain the stem-cell state [111], and the pathway regulated by the oncoprotein c-Myc, which triggers stem cells to give rise to transit amplifying cells [36].
Stem Cells in the Pancreas and Liver
The status of stem cells in the adult pancreas and liver is unclear. During embryonic development, both tissues arise from Endoderm. A recent study indicates that a single precursor cell derived from embryonic endoderm may generate both the ventral pancreas and the liver [23]. In adult mammals, however, both the pancreas and the liver contain multiple kinds of differentiated cells that may be repopulated or regenerated by multiple types of stem cells. In the pancreas, endocrine (hormone-producing) cells occur in the islets of Langerhans. They include the beta cells (which produce insulin), the alpha cells (which secrete glucagon), and cells that release the peptide hormones somatostatin and pancreatic polypeptide. Stem cells in the adult pancreas are postulated to occur in the pancreatic ducts or in the islets themselves. Several recent reports indicate that stem cells that express nestin—which is usually regarded as a marker of neural stem cells—can generate all of the cell types in the islets [60, 113] (see Chapter 7. Stem Cells and Diabetes). The identity of stem cells that can repopulate the liver of adult mammals is also in question. Recent studies in rodents indicate that HSCs (derived from mesoderm) may be able to home to liver after it is damaged, and demonstrate plasticity in becoming into hepatocytes (usually derived from endoderm) [54, 77, 97]. But the question remains as to whether cells from the bone marrow normally generate hepatocytes in vivo. It is not known whether this kind of plasticity occurs without severe damage to the liver or whether HSCs from the bone marrow generate oval cells of the liver [18]. Although hepatic oval cells exist in the liver, it is not clear whether they actually generate new hepatocytes [87, 98]. Oval cells may arise from the portal tracts in liver and may give rise to either hepatocytes [19, 55] and to the epithelium of the bile ducts [37, 92]. Indeed, hepatocytes themselves, may be responsible for the well-know regenerative capacity of liver.
Stem Cells 101
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