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Role of adenosine A2B receptor signaling in contribution of cardiac mesenchymal stem-like cells to myocardial scar formation

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Abstract

Adenosine levels increase in ischemic hearts and contribute to the modulation of that pathological environment. We previously showed that A2B adenosine receptors on mouse cardiac Sca1+CD31− mesenchymal stromal cells upregulate secretion of paracrine factors that may contribute to the improvement in cardiac recovery seen when these cells are transplanted in infarcted hearts. In this study, we tested the hypothesis that A2B receptor signaling regulates the transition of Sca1+CD31− cells, which occurs after myocardial injury, into a myofibroblast phenotype that promotes myocardial repair and remodeling. In vitro, TGFβ1 induced the expression of the myofibroblast marker α-smooth muscle actin (αSMA) and increased collagen I generation in Sca1+CD31− cells. Stimulation of A2B receptors attenuated TGFβ1-induced collagen I secretion but had no effect on αSMA expression. In vivo, myocardial infarction resulted in a rapid increase in the numbers of αSMA-positive cardiac stromal cells by day 5 followed by a gradual decline. Genetic deletion of A2B receptors had no effect on the initial accumulation of αSMA-expressing stromal cells but hastened their subsequent decline; the numbers of αSMA-positive cells including Sca1+CD31− cells remained significantly higher in wild type compared with A2B knockout hearts. Thus, our study revealed a significant contribution of cardiac Sca1+CD31− cells to the accumulation of αSMA-expressing cells after infarction and implicated A2B receptor signaling in regulation of myocardial repair and remodeling by delaying deactivation of these cells. It is plausible that this phenomenon may contribute to the beneficial effects of transplantation of these cells to the injured heart.

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Acknowledgements

This work was supported by the National Institutes of Health National Heart, Lung and Blood Institute [grant R01HL095787 and K08HL094703], National Cancer Institute [grant R01CA138923], American Heart Association Research Grant-in-Aid [13GRNT16580020], and Vanderbilt Clinical and Translational Science Award (CSTA) [grant UL1 RR024975-01] from the National Institutes of Health National Center for Research Resources (Vanderbilt Institute for Clinical and Translational Research CTSA grant VR5622).

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Authors and Affiliations

  1. Divisions of Cardiovascular Medicine (SR, QZ, RJG, IF) and Clinical Pharmacology (IB), Departments of Medicine (SR, QZ, RJG, IB, IF), Cancer Biology (BHS, AW) and Pharmacology (RJG, IB, IF), Vanderbilt University Medical School, Nashville, TN, USA

    Sergey Ryzhov, Bong Hwan Sung, Qinkun Zhang, Alissa Weaver, Richard J. Gumina & Italo Biaggioni

  2. Vanderbilt University, 360 PRB, 2220 Pierce Ave, Nashville, TN, 37232-6300, USA

    Igor Feoktistov

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  1. Sergey Ryzhov
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Correspondence to Igor Feoktistov.

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Ryzhov, S., Sung, B.H., Zhang, Q. et al. Role of adenosine A2B receptor signaling in contribution of cardiac mesenchymal stem-like cells to myocardial scar formation. Purinergic Signalling 10, 477–486 (2014). https://doi.org/10.1007/s11302-014-9410-y

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