76
U N I T 1
Cell and Tissue Function
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).
TABLE 4-1
Growth Factors Involved inTissue Regeneration andWound Healing
Growth Factor
Source
Function
Epidermal growth factor
(EGF)
Activated macrophages, keratinocytes,
and many other cells
Mitogenic for keratinocytes and fibroblasts; simulates
keratinocyte migration and granulation tissue formation
Transforming growth
factor-
α
(TGF-
α
)
Activated macrophages,T lymphocytes,
keratinocytes, and many other cells
Similar to EGF; stimulates replication of hepatocytes and
many epithelial cells
Transforming growth
factor-
β
(TGF-
β
)
Platelets, macrophages,T lymphocytes,
keratinocytes, smooth muscle cells,
fibroblasts
Chemotactic for neutrophils, macrophages, fibroblasts,
and smooth muscle cells; stimulates angiogenesis
and production of fibrous tissue; inhibits proteinase
production and keratinocyte proliferation
Vascular endothelial cell
growth factor (VEGF)
Mesenchymal cells
Increases vascular permeability; mitogenic for endothelial
cells of blood vessels
Platelet-derived growth
factor (PDGF)
Platelets, macrophages, endothelial
cells, keratinocytes, smooth muscle
cells
Chemotactic for neutrophils, macrophages, fibroblasts,
and smooth muscle cells; stimulates production of
proteinases, fibronectin, and hyaluronic acid; stimulates
angiogenesis and wound remodeling
Fibroblast growth factor
(FGF)
Macrophages, mast cells,T
lymphocytes, endothelial cells,
fibroblasts, and many other tissues
Chemotactic for fibroblasts; mitogenic for fibroblasts
and keratinocytes; stimulates angiogenesis, wound
contraction, and matrix deposition
Keratinocyte growth
factor (KGF)
Fibroblasts
Stimulates keratinocyte migration, proliferation, and
differentiation
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