MG53 Promotes Wound Healing and Reduces Scar Formation by Facilitating Cell Membrane Repair and Controlling Myofibroblast Differentiation

Abstract

Cell membrane repair is an important aspect of physiology, and disruption of this process can result in pathophysiology in a number of different tissues including wound healing, chronic ulcer and scaring. We previously identified a novel TRIM (tripartite-motif) family protein, named MG53, as an essential component of the cell membrane repair machinery. Here we report the functional role of MG53 in modulation of wound healing and scarring. Although MG53 is absent from keratinocytes and fibroblasts, remarkable defects in skin architecture and collagen over-production are observed in mg53-/- mice; and these animals display delayed wound healing and abnormal scarring. Recombinant human MG53 (rhMG53) protein, encapsulated in hydrogel formulation, facilitates wound healing and prevents scarring in rodent models of dermal injuries. In vitro study shows that rhMG53 protects against acute injury to keratinocytes and facilitates migration of fibroblasts in response to scratch wounding. During fibrotic remodeling, rhMG53 interferes with TGF-β-dependent activation of myofibroblast differentiation; the resulting down-regulation of alpha smooth muscle actin (α-SMA) and extracellular matrix proteins contributes to reduced scarring. Overall, these studies establish a tri-functional role for MG53 as a facilitator of rapid injury repair, a mediator of cell migration, and a modulator of myofibroblast differentiation during wound healing. Targeting the functional interaction between MG53 and TGF-β signaling may present a potentially effective means for promoting scarless wound healing.