Porth's Essentials of Pathophysiology, 4e

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Cell and Tissue Function

U N I T 1

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In recent years, it has become useful to categorize stem cells into two basic categories: embryonic and adult stem cells. 1,2,5,6 Embryonic stem cells are pluripotent cells derived from the inner cell mass of the blastocyst stage of the embryo. These pluripotent stem cells have the capacity to generate multiple cell lines. As mentioned earlier, unipotential stem cells are normally present in proliferative tissues and generate cell lineages specific to that tissue. It is now recognized, however, that stem cells with the capacity to generate multiple lineages are present in the bone marrow and several other tissues of adult individuals. These cells are called adult stem cells or tissue stem cells. Whether adult stem cells have a dif- ferentiation capacity similar to that of embryonic stem cells remains the subject of current debate and research. 2 Thus far, bone marrow stem cells have been shown to have very broad differentiation capabilities, being able to generate not only blood cells, but also fat, cartilage, bone, endothelial, and muscle cells. A new field of medicine— regenerative medicine —is mainly concerned with the regeneration and restora- tion of damaged organs using embryonic and adult stem cells. 2,6,7 One of the most exciting prospects in this area is a type of stem cell therapy known as therapeutic clon- ing. Other potential therapeutic strategies that use stem cells involve the transplantation of stem cells into areas of injury, mobilization of stem cells from the bone mar- row into injured tissues, and use of stem cell culture systems to produce large amounts of differentiated stem cells for transplantation into injured tissue. Influence of Growth Factors Cell proliferation can be triggered by chemical media- tors including growth factors, hormones, and cyto- kines. 1,2,8–11 The term growth factor is generally applied

to small proteins that increase cell size and cell division. 2 In addition to cell proliferation, most growth factors have other effects. They assist in regulating the inflamma- tory process; serve as chemoattractants for neutrophils, monocytes (macrophages), fibroblasts, keratinocytes, and epithelial cells; stimulate angiogenesis; and contrib- ute to the generation of the ECM. Some growth factors stimulate the proliferation of some cells and inhibit the cycling of other cells. In fact, a growth factor can have opposite effects on the same cell depending on its chang- ing concentration during the healing process. Many of the growth factors are produced by leuko- cytes recruited to the site of injury or activated at the site by the inflammatory process. Other growth factors are produced by parenchymal cells or stromal cells in response to injury or loss. Growth factors are named for their tissue of origin (e.g., platelet-derived growth fac- tor [PDGF], fibroblast growth factor [FGF]), their bio- logic activity (e.g., transforming growth factor [TGF]), or the cells on which they act (e.g., vascular endothelial growth factor [VEGF]). The sources and functions of selected growth factors are described in Table 4-1. The signaling pathways for the growth factors are similar to those of other cellular receptors that recognize extracellular ligands. The binding of a growth factor to its receptor triggers a series of events by which extra- cellular signals are transmitted into the cell, leading to the stimulation or inhibition of gene expression. These genes typically have several functions—they relieve blocks on cell cycle progression (thus promoting cell proliferation), prevent apoptosis, and enhance synthesis of cellular proteins in preparation for mitosis. Signaling may occur in the cell producing the growth factor (auto- crine signaling), in cells in the immediate vicinity of the cell releasing the growth factor (paracrine signaling), or in distant target cells through growth factors that are released into the bloodstream (endocrine signaling). Mitogenic for keratinocytes and fibroblasts; simulates keratinocyte migration and granulation tissue formation Similar to EGF; stimulates replication of hepatocytes and many epithelial cells Chemotactic for neutrophils, macrophages, fibroblasts, and smooth muscle cells; stimulates angiogenesis and production of fibrous tissue; inhibits proteinase production and keratinocyte proliferation Increases vascular permeability; mitogenic for endothelial cells of blood vessels Chemotactic for neutrophils, macrophages, fibroblasts, and smooth muscle cells; stimulates production of proteinases, fibronectin, and hyaluronic acid; stimulates angiogenesis and wound remodeling Chemotactic for fibroblasts; mitogenic for fibroblasts and keratinocytes; stimulates angiogenesis, wound contraction, and matrix deposition Stimulates keratinocyte migration, proliferation, and differentiation Function

Growth Factors Involved inTissue Regeneration andWound Healing

TABLE 4-1

Growth Factor

Source

Epidermal growth factor (EGF) Transforming growth factor- α (TGF- α ) Transforming growth factor- β (TGF- β ) Vascular endothelial cell growth factor (VEGF) Platelet-derived growth factor (PDGF)

Activated macrophages, keratinocytes, and many other cells Activated macrophages,T lymphocytes, keratinocytes, and many other cells Platelets, macrophages,T lymphocytes, keratinocytes, smooth muscle cells, fibroblasts Platelets, macrophages, endothelial cells, keratinocytes, smooth muscle cells Macrophages, mast cells,T lymphocytes, endothelial cells, fibroblasts, and many other tissues Mesenchymal cells

Fibroblast growth factor (FGF)

Keratinocyte growth factor (KGF)

Fibroblasts

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