Matrix control of scarring

Abstract

Repair of wounds usually results in restoration of organ function, even if suboptimal. However, in a minority of situations, the healing process leads to significant scarring that hampers homeostasis and leaves the tissue compromised. This scar is characterized by an excess of matrix deposition that remains poorly organized and weakened. While we know much of the early stages of the repair process, the transition to wound resolution that limits scar formation is poorly understood. This is particularly true of the inducers of scar formation. Here, we present a hypothesis that it is the matrix itself that is a primary driver of scar, rather than being simply the result of other cellular dysregulations.

Fig. 1

Healing by secondary intention involves the closure of a large open defect, and in skin wound healing proceeds through stages that effect repair approaching the original tissue via a wave of signaling factors that orchestrate the cells to generate a paucicellular barrier to the external hostile environment. It is critical that early in the process pro-stimulatory signals recruit cells to replace the lost tissue. However, late in the tissue formation and early in the tissue remodeling phase, other signals are needed to shut off this exuberant response. Growth factors and chemokines function during these phases as “stop” signals. CXCL11/IP-9 is made by redifferentiated keratinocytes that have covered their denuded provisional matrix and CXCL10/IP-10 is produced by nascent blood vessels. These chemokines maintain the de-differentiated state of migrating keratinocytes while causing the dermal fibroblasts to ‘differentiate’ to produce mature matrix. (Note, the initial stage of hemostasis is not shown here)

Fig. 2

CXCR3 signaling axis during wound repair. CXCR3 receptor is a seven transmembrane G protein coupled receptor. This signaling system is extant in human and rodent with the receptor being ubiquitous but the ligands being regulated temporally and spatially. CXCR3 receptor is expressed on keratinocytes, fibroblast, and endothelial cells. CXCL10/IP-10 appears in the dermis and is produced by endothelial cells of the neovasculature and CXCL11/IP-9 is expressed from redifferentiating keratinocytes behind the leading edge of the wound. These secreted peptide factors, both CXC chemokines that lack the canonical N-terminal sequence ELR (glutamic acid-leucine-arginine), bind in common to the ubiquitous CXCR3 chemokine receptor. Signaling through CXCR3 blocks growth factor-induced motility of fibroblasts and endothelial cells by suppressing m-calpain activation. In contrast, these chemokines do not block the motility of dedifferentiated keratinocytes but rather increase their motility via lessened adhesiveness that shifts the cell into the most permissive adhesion/contractility state and thus promotes motility and in turn more rapid re-epithelialization. For endothelial cells, in which the β3 integrin predominates, CXCR3 activation of calpain1/μ-calpain leads to detachment and anoikis

Fig. 3

Process flow representation of wound healing. Usually the process is unidirectional resulting in minimal scarring (Normal). However, in the Absence of ‘stop’ signals (e.g., deficit of CXCR3 signaling) the fibroplasia results in an immature matrix which in turns recruits more inflammatory cells that stimulate the stromal cells to produce more regenerative matrix. This results in a feed-forward loop in which the regenerative matrix is central to driving further scarring. This process slows down when the myofibroblasts contract the matrix, with the fibrosis leading to the death of the excess cells and leaving a fibrotic, sclerotic dermis