MedicalResearch.com Interview with:
Bruno Péault PhD
Professor and Chair, Vascular Regeneration
Center For Cardiovascular Science
MRC Centre for Regenerative Medicine
Scientific Director, BHF Laboratories
The University of Edinburgh and
Professor, David Geffen School of Medicine at UCLA
Orthopaedic Hospital Research Center
University of California at Los Angeles
Los Angeles, CA 90095-7358
MedicalResearch.com: What is the background for this study?
Response: Kidney, lung, liver, muscle, heart are among the many organs which can be severely affected by fibrosis, a natural scarring process whereby healthy tissues are replaced by a fibrous non-functional substitute. For instance, the billions of cardiac muscle cells that die after a heart infarct, consequently to blood supply interruption, are replaced by a fibrotic scar that cannot contract, reducing the capacity of the heart to pump blood, and leading often to heart failure. There is currently no efficient treatment of fibrotic scars, the basic cellular component of which is the myofibroblast, a cell of unremarkable appearance and unclear origin. The transforming growth factor β (TGFβ) molecule triggers fibrosis development after being activated, via the extra-cellular matrix, by αv integrins, which are adhesion molecules present at the surface of the target cells.
To gain further insight into the cells that drive fibrosis in the heart and skeletal muscle, and explore ways to control this deleterious process, mice were used in which cells expressing the β receptor for PDGF (platelet derived growth factor) have been genetically tagged with a green fluorescent protein, a system previously used by Prof. Neil Henderson to trace fibrosis in the diseased liver (cells naturally expressing PDGFRβ are, in their vast majority, perivascular cells surrounding small blood vessels, as well as some interstitial fibroblasts). Skeletal muscle was injured by a small incision or with a targeted injection of cardiotoxin, a snake venom compound that locally kills myofibers, while the heart was damaged by prolonged infusion of angiotensin II. In both settings, progression of fibrosis was followed over time and contribution of green fluorescent cells – i.e. those expressing PDGFRβ – was assessed.
MedicalResearch.com: What are the main findings?
Response: In both skeletal and heart muscles, the fibrotic scar was contributed by cells expressing PDGFRβ. This showed, for the first time, the role of perivascular/interstitial PDGFRβ+ mesenchymal cells in the fibrotic degeneration of these organs. Strategies were next devised to interact with αv integrins expressed by these cells, in attempts to counteract fibrosis development.
First, αv integrins were genetically eliminated from the surface of PDGFRβ+ cells, which resulted in a very significant decrease in fibrosis. In a more clinically relevant approach, PDGFRβ reporter mice injured in the skeletal muscle or heart were administered a small molecule, CWHM 12, known to inhibit αv integrins. Here again, fibrosis was dramatically diminished. Importantly, this anti-fibrotic effect was observed when CWHM 12 was administered either prophylactically, prior to injury, or therapeutically post injury.
MedicalResearch.com: What should readers take away from your report?
Response: These basic investigations on a severe, currently untreatable condition affecting the acutely injured skeletal and cardiac muscles have shed light on the identity of the cells at the origin of fibrosis. Moreover, this work has showed that pharmacologic inhibition of the αv integrin adhesion molecules, which play a key role in the onset of the fibrotic process, can dramatically reduce the development of the fibrotic scar. This is an encouraging early step toward the development of a treatment for this debilitating condition.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: The identification of PDGFRβ expressing cells at the origin of fibrosis in the skeletal and cardiac muscles marks a progress; however much more work is needed to understand the exact identity of these cells, inasmuch as PDGFRβ+ cells are heterogeneous and include, in addition to pericytes, less defined mesenchymal cells. Unpublished results obtained recently at UCLA with some of our colleagues, principally Drs Ayelet Dar and Frank Petrigliano, indicate that distinct combinations of PDGF α and β receptors allow for the distinction between regenerative and pro-fibrotic cells, narrowing down to a smaller subset of PDGFRβ+ cells the “bad” cells responsible for fibrosis. Animal transplantation experiments will show whether such purified non-fibrogenic progenitor cells can be used as therapies of the critically injured skeletal muscle.
Inhibition of muscle and cardiac fibrosis by the αv integrin blocking agent CWHM 12 is at an early experimental stage and must be the object of multiple investigations in diverse systems in vivo regarding dosage, route of administration, target indications (acute or chronic injury), secondary and long-term effects.
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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. αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis. Nature Communications, 2017; 8 (1) DOI: 10.1038/s41467-017-01097-z
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