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

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  • 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

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    License: Creative Commons: Attribution (CC-BY)

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


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.

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