Preventing tissue fibrosis by local biomaterials interfacing of specific cryptic extracellular matrix information

Nat Commun. 2017 Jun 8:8:15509. doi: 10.1038/ncomms15509.

Abstract

Matrix metalloproteinases (MMPs) contribute to the breakdown of tissue structures such as the basement membrane, promoting tissue fibrosis. Here we developed an electrospun membrane biofunctionalized with a fragment of the laminin β1-chain to modulate the expression of MMP2 in this context. We demonstrate that interfacing of the β1-fragment with the mesothelium of the peritoneal membrane via a biomaterial abrogates the release of active MMP2 in response to transforming growth factor β1 and rescues tissue integrity ex vivo and in vivo in a mouse model of peritoneal fibrosis. Importantly, our data demonstrate that the membrane inhibits MMP2 expression. Changes in the expression of epithelial-to-mesenchymal transition (EMT)-related molecules further point towards a contribution of the modulation of EMT. Biomaterial-based presentation of regulatory basement membrane signals directly addresses limitations of current therapeutic approaches by enabling a localized and specific method to counteract MMP2 release applicable to a broad range of therapeutic targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biocompatible Materials / chemistry*
  • Disease Models, Animal
  • Epithelial Cells / metabolism
  • Epithelial-Mesenchymal Transition / genetics
  • Epithelium / metabolism
  • Extracellular Matrix / metabolism*
  • Gene Expression Profiling
  • HEK293 Cells
  • Humans
  • Integrin alpha3beta1 / metabolism
  • Laminin / metabolism
  • Mammary Glands, Human / cytology
  • Matrix Metalloproteinase 2 / metabolism
  • Membranes, Artificial
  • Mice
  • Peritoneal Fibrosis / metabolism*
  • Peritoneal Fibrosis / pathology*
  • Peritoneum / metabolism
  • Protein Binding
  • Signal Transduction

Substances

  • Biocompatible Materials
  • Integrin alpha3beta1
  • Laminin
  • Membranes, Artificial
  • Matrix Metalloproteinase 2