Skin tissue repair: Matrix microenvironmental influences

Abstract

The process of repair of wounded skin involves intricate orchestration not only between the epidermal and dermal compartments but also between the resident and immigrant cells and the local microenvironment. Only now are we beginning to appreciate the complex roles played by the matrix in directing the outcome of the repair processes, and how this impacts the signals from the various cells. Recent findings speak of dynamic and reciprocal interactions that occurs among the matrix, growth factors, and cells that underlies this integrated process. Further confounding this integration are the physiologic and pathologic situations that directly alter the matrix to impart at least part of the dysrepair that occurs. These topics will be discussed with a call for innovative model systems of direct relevance to the human situation.

Keywords: Chronic wound; Collagen; Decorin; Extracellular matrix; Matrikine signaling; Skin organ cultures; Tenascin-C; Wound healing.

Figure 1. Phase transitions in excisional wound healing and dysrepair

Wound healing proceeds from the initial homeostatic phase through tissue regeneration and into resolution. While these phases overlap both temporally and spatially within a wound, the orchestrated progression leads to re-established functioning with minimal scarring (left sequence). If the resolution phase has excessive cellularity and matrix from an over exuberant tissue replacement phase that lacks stop signals, this is not a stable phenotype. The renewal of an active immature matrix in the resolution phase results in excessive tissue and hypertrophic scars or even keloids (middle sequence). When the homeostatic phase does not transition towards regeneration, the healing is stalled and the initial, tissue-destructive inflammation persists. This situation leads to a chronic wound or ulcer (right sequence).

Figure 2. Key players during different stages of wound repair

The hemostasis (day 2), tissue replacement (day 10) and resolving (day 30) phases of healing are schematized here. Highlighted in each stage (and identified below) are the main cells and matrix/matricellular components that constitute that stage. (please note that the basement membrane is greatly exaggerated in size).

Figure 3. The ‘scarring cycle’ schematized

Hypertrophic scars are regenerated from a persistence of the tissue replacement phase, in the absence of ‘stop signals’ such as ligands for CXCR3 or angiopoietins even after full re-epithelialization and seeming ‘wound closure’ (right arm). This hypercellularity with active matrix turnover re-initiates an chronic inflammatory milieu which in turns drive more immature matrix production, eventually leading to excessive but poorly functional fibrillar collagen. Adapted from ref .