Journal Article

αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis

Gonzalez, Z. N., Dobie, R., Mackinnon, A. C., Baily, J., Wallace, R. J., Singh, M., Conroy, K. P., Gray, G. A., Murray, I. R., Li, Y., Smith, J. R., Thompson, A. I., Dai, J., Campbell, M. A., Kendall, T. J., Greenhalgh, S. N., Iredale, J. P., Simpson, H., Griggs, D. W., Henderson, N. C., Ruminski, P. G., Huard, J., Péault, B.

2017

Overview

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. The mechanisms underlying tissue fibrosis are unclear. The authors show that mesenchymal cells expressing PDGFRβ mediate fibrosis in skeletal muscle and heart via a mechanism involving αv integrin, and that inhibitors of αv integrins attenuate fibrotic responses in mice.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/250/127/1219 / 631/80/84/2342 / 692/698/1671/1668/1973 / 692/699/75/230 / Angiotensin / Angiotensin II / Animals / Apoptosis / Cardiac muscle / Cell Movement / Cells, Cultured / Collagen - metabolism / Fibrosis / Genotype / Heart / Heart diseases / Humanities and Social Sciences / Humans / Inhibitors / Integrin alphaV - metabolism / Integrins / Kidneys / Liver / Male / Mesenchymal Stem Cells - cytology / Mesenchyme / Mice / Mice, Inbred C57BL / Mice, Transgenic / multidisciplinary / Muscle, Skeletal - pathology / Musculoskeletal system / Myocardium - pathology / Organs / Platelet-derived growth factor / Receptor, Platelet-Derived Growth Factor beta - genetics / Receptor, Platelet-Derived Growth Factor beta - metabolism / Recombinant Proteins - metabolism / Rodents / Science / Science (multidisciplinary) / Skeletal muscle