625 Fibroblast-specific overexpression of collagen XII leads to a delay in skin repair

Abstract

FACIT collagen XII decorates large collagen fibrils within stiff connective tissues. While its mutation or loss causes disorders of connective tissues in humans, its overabundance was described in fibrotic lesions of scleroderma patients and corneal scarring, indicating a vital role of collagen XII in ECM homeostasis. We postulate that collagen XII has the potential to influence tissue properties by linking scaffolding molecules, transmitting signals to cells or by modulating availability of growth factors. We study the roles of dermal collagen XII during reconstitution of the skin following excisional wounding in mice with fibroblast-specific overexpression of collagen XII and controls. In controls, collagen XII was abundantly deposited into early granulation tissue and persisted at high levels throughout the healing process. The overexpressing mice showed delayed wound healing with enlarged, more cell dense granulation tissue. The number of macrophages was significantly increased. Characterization of macrophage subpopulations revealed that in the collagen XII overexpressing mice, the macrophages maintained an early wound healing (M1-like) phenotype, indicating that overall wound healing was delayed. In vitro interaction studies between macrophages and collagen XII showed that only M1, but not unstimulated or M2 polarized macrophages were able to adhere to collagen XII. These findings led to the hypothesis that overproduction of collagen XII favors selective adhesion and persistent presence of M1 polarized, pro-inflammatory macrophages causing a delay in the healing process and possibly more severe scarring. Our future work will identify the receptors mediating the selective adhesion of M1 polarized macrophages to collagen XII and characterize scar tissue maturity at late stages of the healing process.