Modulation of Wound Healing and Scar Formation by MG53 Protein-Mediated Cell Membrane Repair

J Biol Chem. 2015 Oct 2;290(40):24592-603. doi: 10.1074/jbc.M115.680074. Epub 2015 Aug 25.

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.

Keywords: TGF-β; cell migration; fibrosis; myofibroblast; recombinant human MG53 protein; thermosensitive hydrogel; wound healing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3T3 Cells
  • Actins / metabolism
  • Animals
  • Carrier Proteins / physiology*
  • Cell Differentiation
  • Cell Membrane / metabolism*
  • Cell Movement
  • Cicatrix / pathology
  • Collagen Type I / metabolism
  • Fibroblasts / cytology
  • Fibronectins / metabolism
  • Fibrosis / pathology
  • Gene Expression Regulation
  • Humans
  • Hydrogels / chemistry
  • Keratinocytes / metabolism
  • Membrane Proteins
  • Mice
  • Muscle Proteins / physiology*
  • Muscle, Smooth / metabolism
  • Myofibroblasts / metabolism
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / metabolism
  • Skin / pathology
  • Tripartite Motif Proteins
  • Vesicular Transport Proteins / physiology*
  • Wound Healing / physiology*

Substances

  • Actins
  • Carrier Proteins
  • Collagen Type I
  • Fibronectins
  • Hydrogels
  • MG53 protein, mouse
  • Membrane Proteins
  • Muscle Proteins
  • Recombinant Proteins
  • TRIM72 protein, human
  • TRIM72 protein, rat
  • Tripartite Motif Proteins
  • Vesicular Transport Proteins