Biomedical Engineering Reference
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facilitates keratinocyte migration in dermal matrix by weakening the interactions
between collagen and integrins [
46
]. MMP-10 (stromelysin-2) is colocalized with
MMP-1 while MMP-3 (stromelysin-1) is localized in the cells behind the migration
wave. Lack of superposition between MMP-3 and -10 (even if they are MMPs with
similar structure) suggests that MMPs are playing various roles in re-epithelization
processes [
103
]. MMP-7 regulates re-epithelization by cleavage of E-cadherins in
adherence junctions, thus facilitating cell migration. MMP-28 (epilysin) is expressed
by keratinocytes localized distally from injured area and lacks from migrating kera-
tinocytes. This suggests a possible role in reorganization of the basement membrane
or in cleavage of the adhesion molecules, releasing new cells for the migration wave
[
103
]. MMP-9 (gelatinase B) is also involved in re-epithelization process following
local injury [
76,
78,
95
]. Epidermal growth factor (EGF) and hepatocyte growth
factor (HGF) stimulate the keratinocyte migrating ability. Cell migration depends
on the MMP-9 activation and it is modulated by TIMPs or by synthetic specific
inhibitors. MMP-10 is expressed by epithelial cells in the migrating cell wave and
its over-expression may induce aberrant cell migration at wound edge level, reduc-
ing the abundance of laminin-5 mainly by direct cleavage. Laminin-5 decreased
levels are associated with impairment of the cell-matrix signaling pathways and
increase the number of keratinocytes that undergo apoptosis. Proliferation of the
epithelial cells behind cell migration wave in the injured area is regulated by MMP-
14. It appears that this MMP activity is directly related to keratinocyte growth factor
receptors processing during epithelial injury repair. Thus, wound healing is similar
to tissue morphogenesis processes that include cell migration, proliferation, differ-
entiation, and cell death [
59,
104
] .
2.8
MMP Involvement in Resolution Step of Wound Healing
It appears that MMP-3 may influence reorganization of actin filaments in dermal
cultured fibroblasts that initiates early injured area contraction. It appears that ECM
remodeling processes depend on various MMPs as MMP-1, -3, -13, and -14,
enzymes that are able to cleave collagen. Also, MMP-7 may process syndecan or
elastin. Collagen remodeling that includes degradation of preexistent fibrils and
synthesis of new ones represent the main process in wound resolution. The enzymes
involved in this process appear to be MMP-2 and -9 together with MMP-3 that are
localized at epithelial-stromal interface, behind the epithelial cell migration wave,
that suggests involvement in stromal and basement membrane remodeling [
85
] .
2.9
TIMPs in Wound Repair
Inflammatory response is mediated by multiple cytokines and chemokines. Among
cytokines involved in acute inflammation, TNF-alpha is activated by cleavage at
membrane level by the specific conversion enzyme. One effect on inflammatory
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