Adenosine A2B receptors on cardiac stem cell antigen (Sca)-1-positive stromal cells play a protective role in myocardial infarction

Abstract

Transplantation of mesenchymal stem-like cells to the heart is known to improve cardiac recovery in animal models of myocardial infarction (MI). Because stimulation of A2B adenosine receptors on mouse cardiac stem cell antigen (Sca)-1(+)CD31(-) mesenchymal stem-like cells significantly up-regulates their secretion of pro-angiogenic factors, we hypothesized that ablation of the A2B receptor signaling in these cells would reduce their ability to improve vascularization of the infarct area seen after transplantation. Wild-type (WT) C57BL/6 mice underwent permanent left coronary artery ligation and received intramyocardial injections of Sca-1(+)CD31(-) cells generated from WT or A2B receptor knockout (A2BKO) mice or the same volume of cell-free saline. Only 12% to 16% of injected cells remained in the ventricles 1 week later; there was no significant difference between WT and A2BKO cell survival. Transplantation of WT, but not A2BKO, cells significantly reduced both post-MI decline in cardiac function and adverse remodeling compared with that seen in control hearts. Morphological analysis conducted 4 weeks after MI revealed significantly increased vascularization of the infarct areas and reduced myocardial scarring in animals treated with WT, but not with A2BKO, cells compared with control. Thus, our study demonstrated that the A2B receptor signaling linked to up-regulation of pro-angiogenic factors in cardiac Sca-1(+)CD31(-) stromal cells is essential for overall improvement of cardiac recovery seen after their transplantation to the injured heart.