αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis

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

doi:10.1038/s41467-017-01097-z

αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis

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

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

Original language	English
Article number	1118
Number of pages	13
Journal	Nature Communications
Volume	8
Early online date	24 Oct 2017
DOIs	https://doi.org/10.1038/s41467-017-01097-z
Publication status	Published - 24 Oct 2017

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s41467-017-01097-z
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DO NOT REPORT: BHF UK Cardiovascular Regenerative Medicine Centre
Baker, A.
UK-based charities
1/10/15 → 30/09/17
Project: Research
Therapeutic targeting of myofibroblasts in skeletal muscle fibrosis¿
Murray, I.
UK-based charities
1/08/15 → 31/05/17
Project: Research
An intravital imaging approach to elucidate novel mechanisms of organ fibrosis and repair
Henderson, N.
UK-based charities
1/08/14 → 31/01/20
Project: Research

Stephen Greenhalgh
- Stephen.Greenhalghed.acuk
- Royal (Dick) School of Veterinary Studies - Lecturer in Animal Bioscience
Person: Academic: Research Active
Bruno Peault
Person: Academic: Research Active
Hamish Simpson
- Edinburgh Imaging
- Centre for Inflammation Research
Person: Academic: Research Active

Cite this

Murray, I. R., Gonzalez, Z. N., Baily, J., Dobie, R., Wallace, R. J., Mackinnon, A. C., Smith, J. R., Greenhalgh, S. N., Thompson, A. I., Conroy, K. P., Griggs, D. W., Ruminski, P. G., Gray, G. A., Singh, M., Campbell, M. A., Kendall, T. J., Dai, J., LI, Y., Iredale, J. P., ... Henderson, N. C. (2017). αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis. Nature Communications, 8, Article 1118. https://doi.org/10.1038/s41467-017-01097-z

@article{0344ba1984db494e959d2925995d8599,

title = "αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis",

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.",

author = "Murray, {I. R.} and Gonzalez, {Z. N.} and J. Baily and R. Dobie and Wallace, {R. J.} and Mackinnon, {A. C.} and Smith, {J. R.} and Greenhalgh, {S. N.} and Thompson, {A. I.} and Conroy, {K. P.} and Griggs, {D. W.} and Ruminski, {P. G.} and Gray, {G. A.} and M. Singh and Campbell, {M. A.} and Kendall, {T. J.} and J. Dai and Y. LI and Iredale, {J. P.} and H. Simpson and J. Huard and B. P{\'e}ault and Henderson, {N. C.}",

year = "2017",

month = oct,

day = "24",

doi = "10.1038/s41467-017-01097-z",

language = "English",

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journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Murray, IR, Gonzalez, ZN, Baily, J, Dobie, R, Wallace, RJ, Mackinnon, AC, Smith, JR, Greenhalgh, SN, Thompson, AI, Conroy, KP, Griggs, DW, Ruminski, PG, Gray, GA, Singh, M, Campbell, MA, Kendall, TJ, Dai, J, LI, Y, Iredale, JP, Simpson, H, Huard, J, Péault, B & Henderson, NC 2017, 'αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis', Nature Communications, vol. 8, 1118. https://doi.org/10.1038/s41467-017-01097-z

TY - JOUR

T1 - αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis

AU - Murray, I. R.

AU - Gonzalez, Z. N.

AU - Baily, J.

AU - Dobie, R.

AU - Wallace, R. J.

AU - Mackinnon, A. C.

AU - Smith, J. R.

AU - Greenhalgh, S. N.

AU - Thompson, A. I.

AU - Conroy, K. P.

AU - Griggs, D. W.

AU - Ruminski, P. G.

AU - Gray, G. A.

AU - Singh, M.

AU - Campbell, M. A.

AU - Kendall, T. J.

AU - Dai, J.

AU - LI, Y.

AU - Iredale, J. P.

AU - Simpson, H.

AU - Huard, J.

AU - Péault, B.

AU - Henderson, N. C.

PY - 2017/10/24

Y1 - 2017/10/24

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-017-01097-z

DO - 10.1038/s41467-017-01097-z

M3 - Article

C2 - 29061963

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 1118

ER -

αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis

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Projects

DO NOT REPORT: BHF UK Cardiovascular Regenerative Medicine Centre

Therapeutic targeting of myofibroblasts in skeletal muscle fibrosis¿

An intravital imaging approach to elucidate novel mechanisms of organ fibrosis and repair

Profiles

Stephen Greenhalgh

Bruno Peault

Hamish Simpson

Cite this