Abstract
There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure. We have recently shown that cardiac fibrosis post-myocardial infarction (MI) can be regulated by resident cardiac cells with a fibrogenic signature and identified by the expression of PW1 (Peg3). Here we identify αV-integrin (CD51) as an essential regulator of cardiac PW1+ cells fibrogenic behavior. We used transcriptomic and proteomic approaches to identify specific cell-surface markers for cardiac PW1+ cells and found that αV-integrin (CD51) was expressed in almost all cardiac PW1+ cells (93% ± 1%), predominantly as the αVβ1 complex. αV-integrin is a subunit member of the integrin family of cell adhesion receptors and was found to activate complex of latent transforming growth factor beta (TGFβ at the surface of cardiac PW1+ cells. Pharmacological inhibition of αV-integrin reduced the profibrotic action of cardiac PW1+CD51+ cells and was associated with improved cardiac function and animal survival following MI coupled with a reduced infarct size and fibrotic lesion. These data identify a targetable pathway that regulates cardiac fibrosis in response to an ischemic injury and demonstrate that pharmacological inhibition of αV-integrin could reduce pathological outcomes following cardiac ischemia.
Highlights
There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure
This combined approach led to the identification of αV-integrin (CD51, encoded by Itgav) which is detectable in > 90% of cardiac PW1+ cells. αV-integrin is a subunit member of the integrin family of cell adhesion receptors and previous studies show that these molecules are central mediators of organ fibrosis through the TGF-beta signaling p athway[22,23]
We used the same strategy to define the surface membranome of other cell types, including cardiomyocytes (CMs), non-myocytes heart fractions, and mouse embryonic stem cells, and performed a final screen to limit our list to 378 candidates, which were present in the datasets obtained from cardiac PW1+ cells (Fig. 1C)
Summary
There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure. Proliferation of resident fibroblasts[15], transformation of endothelial and/or epicardial cells after injury through endothelial-mesenchymal transition and epithelial–mesenchymal transition r espectively[16,17], and migration of hematopoietic bone marrow-derived cells and perivascular cells[18] Another model proposes the activation of tissue-resident progenitor populations in response to stress that serves as a major cellular source of organ fibrosis, including the heart. We described a novel population of cardiac stromal cells that resides in the myocardium and exhibits a fibrogenic fate in response to cardiac ischemic injury[19] This population was identified based on the expression of the pan-stem cell marker, Pw1/Peg[3] (referred hereafter as PW1)[20,21], using a transgenic Pw1-beta galactosidase (β-gal) reporter mouse model (Pw1nLacZ). We found that αV-integrin is directly involved in directing the fibrogenic cell fate of cardiac PW1+ cells and the blockade of αV-integrin results in a marked reduction in cardiac PW1+ fibrotic activation as well as in cardiac fibrosis post-myocardial infarction (MI) in vivo
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