The Wound Repair Response
Disruption of the stratum
corneum layer results in a loss of barrier function
and elicits a homeostatic response designed to restore it
"fast and well". In a situation involving full-thickness
injury to the skin, wound closure is brought about by mechanisms
involving both the epithelium and the connective tissue
underneath (known as dermis). Thus, epithelial cells located
proximal to the wound site are recruited to migrate along
the interface between the hemostatic plug (blood clot) and
the provisional tissue matrix. Dermal fibroblasts located
proximal to the wound site are recruited as well for differentiation
into myofibroblasts and migration underneath the hemostatic
plug, where their coordinated contraction leads to a pulling
effect that brings the edges of the wound towards its center.
This concerted action on the part of epithelial cells, which
migrate, and dermal
fibroblasts, which "populate" and then contract, ensures
that the wound surface recovers an epithelial lining (along
with suitable barrier properties) as soon as possible .
Other processes, such as angiogenesis and extracellular
matrix deposition, also play a central role during successful
wound closure. It is worth noting that hair and glandular
epithelia are not regenerated when completely destroyed
by the injury process.
The term keratinocyte
activation has been coined to describe the early phase
following skin injury during which keratinocytes located
proximal to the wound edge re-tool themselves to shift their
realm of competency from one dedicated to terminal differentiation
into one compatible with migration into the wound site.
At the electron microscope level, activation amounts to
a striking hypertrophy, a reorganization of keratin tonofilaments,
a decrease in cell-cell adhesion, and the appearance of
cell surface projections. Molecularly, activation coincides
with the induction of a growing list of genes whose products
are known to affect keratinocytes in profound ways. Included
among them, for instance, are proteins that play a critical
role during keratinocyte migration within a fibrin- and
fibrinogen-rich matrix, such as integrins, matrix metalloproteinases
and collagenases, and the urokinase-type plasminogen activator
and its receptor. Also included in this list are the K6,
K16 and K17
genes, which we study in this laboratory (for an example
involving K16 follow this link).
This activation phase precedes the actual
onset of keratinocyte migration, which typically begins
at 18-24 hours following injury. Keratinocyte migration
occurs in the form of a stratified sheet of epithelial
tissue, implying a special type of intercellular coordination
and a heightened dynamism at the level of cell-cell and
cell matrix contacts. In a way, the skin keratinocyte involved
in wound repair is likely to be considerably more plastic
than normal. Hence the idea that similar to other tissues
such as liver, there may exist a molecular relationship
between wound repair in adult skin and aspects of its embryonic
development. The following unresolved issues are of particular
interest to our laboratory:
(a) How are
keratinocytes at the wound edge recruited to participate
to re-epithelialization ? In other words, "what" leads to
keratinocyte
activation, and "how" does it occur ?
(b) How significant
is the relationship between the activated keratinocyte at
the wound edge, the diseased keratinocyte within psoriatic
or cancerous lesions, and the embryonic epithelial cell
in developing skin ?
(c) What role(s)
do keratins play
in this process ?
