\u03b1v integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis

Iain R Murray ,David W Griggs ,Peter Ruminski ,John P Iredale ,Manvendra K Singh ,Kylie P Conroy ,Stephen N Greenhalgh ,Mary Ann Campbell ,Zaniah González ,Ross Dobie ,Hamish Simpson ,Johnny Huard ,Jia Dai ,Yong Li ,James Baily ,Bruno Péault ,Alison C Mackinnon ,Robert Wallace ,Alexandra Thompson ,Timothy J Kendall ,Gillian A Gray ,J F Smith ,Neil C Henderson

doi:10.1038/s41467-017-01097-z

Abstract

Mesenchymal cells expressing platelet-derived growth factor receptor beta (PDGFRβ) are known to be important in fibrosis of organs such as the liver and kidney. Here we show that PDGFRβ+ cells contribute to skeletal muscle and cardiac fibrosis via a mechanism that depends on αv integrins. Mice in which αv integrin is depleted in PDGFRβ+ cells are protected from cardiotoxin and laceration-induced skeletal muscle fibrosis and angiotensin II-induced cardiac fibrosis. In addition, a small-molecule inhibitor of αv integrins attenuates fibrosis, even when pre-established, in both skeletal and cardiac muscle, and improves skeletal muscle function. αv integrin blockade also reduces TGFβ activation in primary human skeletal muscle and cardiac PDGFRβ+ cells, suggesting that αv integrin inhibitors may be effective for the treatment and prevention of a broad range of muscle fibroses.

Highlights

Transforming growth factor beta (TGFβ) is a key profibrogenic cytokine in multiple organs including skeletal muscle and heart[12,13,14]
We established that selective depletion of αv integrins on PDGFRβ+ cells protects mice from fibrosis in both these muscle types, and αv integrin depletion on PDGFRβ+ cells had no adverse effects on skeletal muscle regeneration
We found that Pdgfrb-Cre effectively targeted quiescent PDGFRβ+ cells and activated myofibroblasts in both skeletal and cardiac muscle

Summary

Introduction

Transforming growth factor beta (TGFβ) is a key profibrogenic cytokine in multiple organs including skeletal muscle and heart[12,13,14]. The molecular pathways regulating local activation of TGFβ at the site of injury and fibrogenesis represent attractive targets for novel anti-fibrotic therapies. We exploited a recently developed genetic system (Pdgfrb-Cre) in mice to identify molecular mechanisms driving skeletal and cardiac muscle fibrosis, and focussed on the integrin αv subunit because of the aforementioned role of αv integrins in activating latent TGFβ, a central mediator of fibrosis. In addition to a genetic approach, we investigated the utility of a small molecule inhibitor of αv integrins (CWHM 12) as a potential anti-fibrotic therapy for both skeletal and cardiac muscle fibrosis. Treatment with CWHM 12 attenuates fibrosis in both skeletal muscle and heart, even after the fibrotic process is established

Methods

Results

Conclusion