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 scarring. We have previously identified a novel tripartite motif family protein, MG53, as an essential component of the cell membrane repair machinery. Here we report the functional role of MG53 in the modulation of wound healing and scarring. Although MG53 is absent from keratinocytes and fibroblasts, remarkable defects in skin architecture and collagen overproduction are observed in mg53(-/-) mice, and these animals display delayed wound healing and abnormal scarring. Recombinant human MG53 (rhMG53) protein, encapsulated in a hydrogel formulation, facilitates wound healing and prevents scarring in rodent models of dermal injuries. An in vitro study shows that rhMG53 protects against acute injury to keratinocytes and facilitates the 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 α smooth muscle actin and extracellular matrix proteins contributes to reduced scarring. Overall, these studies establish a trifunctional 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.
Highlights
MG53 is a membrane repair gene whose role in wound healing has not been studied
We show that treatment of fibroblasts with Recombinant human MG53 (rhMG53) leads to reduced expression of ␣-SMA, collagen 1, and fibronectin, which may contribute to the reduction of scarring during wound healing
We show that MG53 has therapeutic benefits in treating dermal wounds
Summary
MG53 is a membrane repair gene whose role in wound healing has not been studied. Results: Topical administration of MG53 protein facilitates wound healing and reduces scar formation. The resulting down-regulation of ␣ smooth muscle actin and extracellular matrix proteins contributes to reduced scarring Overall, these studies establish a trifunctional role for MG53 as a facilitator of rapid injury repair, a mediator of cell migration, and a modulator of myofibroblast differentiation during wound healing. Cell membrane injury repair is an important aspect of normal physiology, and its disruption can result in various pathologies, including insufficient wound healing, chronic ulcers, and scarring [1,2,3, 12,13,14,15]. MG53 is capable of nucleating the cell membrane repair machinery, protecting from acute and stress-induced injuries to the epidermis Such a fast membrane resealing response could reduce the overall inflammatory responses during the early phase of wounding and facilitate early closure of the wound and impact the fibrotic remodeling during later stages of healing. We show that treatment of fibroblasts with rhMG53 leads to reduced expression of ␣-SMA, collagen 1, and fibronectin, which may contribute to the reduction of scarring during wound healing
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