Edinburgh Research Explorer

αv integrins on mesenchymal cells critically regulate skeletal and cardiac muscle fibrosis

Research output: Contribution to journalArticle

  • Z N Gonzalez
  • J R Smith
  • Stephen Greenhalgh
  • A L Thompson
  • David Griggs
  • Peter Ruminski
  • G A Gray
  • M Singh
  • M A Campbell
  • J Dai
  • Y LI
  • Johnny Huard

Related Edinburgh Organisations

Access status

Open

Documents

  • Download as Adobe PDF

    Rights statement: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

    Final published version, 4 MB, PDF-document

    License: Creative Commons: Attribution (CC-BY)

Original languageEnglish
JournalNature Communications
Early online date24 Oct 2017
DOIs
StateE-pub ahead of print - 24 Oct 2017

Abstract

Muscle fibrosis is a major global healthcare burden, with excessive myofibroblast deposition of extracellular matrix proteins a hallmark of skeletal and cardiac muscle fibrosis. While mesenchymal cells expressing platelet-derived growth factor receptor beta (PDGFRβ) are known to be important in fibrosis of solid organs such as the liver and kidney, their contribution to skeletal and cardiac muscle fibrogenesis remains unclear. Using PDGFRβ-Cre mice, we identified a core cellular and molecular pathway driving both skeletal and cardiac muscle fibrosis, focussing on αv integrins and their activation of transforming growth factor beta (TGFβ), a central mediator of fibrosis. PDGFRβ-Cre effectively targeted quiescent PDGFRβ+ cells and activated
49 myofibroblasts in both skeletal and cardiac muscle. αv integrin depletion on PDGFRβ+ cells protected mice from cardiotoxin and laceration-induced skeletal muscle fibrosis and angiotensin II-induced cardiac fibrosis. In addition, a small-molecule inhibitor of αv integrins attenuated fibrosis, even when pre-established, in both skeletal and cardiac muscle and improved skeletal muscle function. αv integrin blockade also reduced TGFβ activation in primary human skeletal muscle and cardiac PDGFRβ+ cells, further highlighting the potential clinical utility of small molecule αv integrin inhibition in the treatment and prevention of a broad range of muscle fibroses.

Download statistics

No data available

ID: 42494871