Connective Tissue Formation in Wound Healing - E-thesis

and discoidin domain receptors monitor the integrity of the collagenous extracellular matrix by
triggering matrix degradation and renewal (203). Two of the best known collagen receptors are
members of the integrin family, α1β1 and α2β1 (204). The α1β1 integrin is abundant on
smooth muscle cells, whereas α2β1 is the collagen receptor on platelets and epithelial cells.
Many cell types, including fibroblasts, chondrocytes, osteoblast, endothelial cells, and
lymphocytes may express both of the receptors simultaneously. The integrins are connected to
cellular signaling pathways. The shape of the matrix and ultimately the shape of the cell can
modify signaling events (204-206).
Cell movement, occurring during tissue repair, depends on integrin-mediated interactions
(207). Integrins physically link the ECM to the cytoskeleton, and hence are responsible for
establishing a mechanical continuum by which forces are transmitted between the outside and
the inside of cells in both directions (208). Fibroblasts embedded in a restrained collagen
lattice transmit mechanical forces by integrin receptors (200). This interaction results in the
induction of growth factors including TGF-βs and CTGF and in enhanced collagen production.
Simultaneously, the expression of MMP-1 and MT1-MMP is down-regulated, resulting in an
overall ECM synthesis favoring phenotype (200). During wound healing process α1β1 integrin
expression is down-regulated and α2β1 integrin expression is up-regulated in fibroblasts. This
is due to the action of PDGF and TGF-β (32, 209).
Myofibroblasts are a particular phenotype of granulation tissue fibroblasts which show an
abundant rough endoplasmic reticulum and usually express α-smooth muscle (α-SM) actin
(210). Morphologically, myofibroblasts are characterized by a contractile apparatus that
contains bundles of actin microfilaments with associated contractile proteins such as nonmuscle
myosin, and which is analogous to stress fibers that have been described in cultured
fibroblasts (211). These actin bundles terminate at the myofibroblast surface in the fibronexus
– a specialized adhesion complex that uses transmembrane integrins to link intracellular actin
with extracellular fibronectin fibrils, a phenomenon not found in normal fibroblasts (211, 212).
Functionally, this provides a system where the force generated by stress fibers can be
transmitted to the surrounding ECM (211). In addition, extracellular mechanical signals can be
transduced into intracellular signals through this system (199, 211). There are two types of
myofibroblasts: those that do not express α-SM actin, which is termed “proto-myofibroblasts”;
and those that do express α-smooth muscle actin, which is termed “differentiated
myofibroblasts” (212). In normal tissues, proto-myofibroblasts are always present when there
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