Abstract 19248: Exosomal miR-142 Derived From Diabetic Bone Marrow Endothelial Progenitor Cells Impairs Cardiac Reparative Abilities Post Myocardial Infarction

• Published in: Circulation (New York, N.Y.) Vol. 134; no. Suppl_1 Suppl 1; p. A19248
• Main Authors: Garikipati, Venkata N, Khan, Mohsin, Verma, Suresh K, Cheng, Zhongjian, Yue, Yujia, Nickoloff, Emily, Benedict, Cindy, Gao, Erhe, Goukassian, David, Kishore, Raj
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 11.11.2016
• ISSN: 0009-7322; 1524-4539

IntroductionDiabetes is associated with a higher incidence of myocardial infarction (MI). Bone marrow-derived endothelial progenitor cell (EPCs) therapy has been shown to attenuate left ventricular (LV) dysfunction after diabetic MI. Recently the therapeutic performance of stem cells is reported to be largely mediated via exosomes (Exo). However, the autologous transplantation of EPCs in patients with diabetes, which is a common background disease in patients with ischemic heart diseases, yielded modest results, suggesting the compromised cell functions.HypothesisTherefore, we hypothesized that, impaired functional benefits of diabetic EPCs are due to altered exosomal contents and whether modulation of identified targets like specific microRNAs in exosomal cargo can rescue and/or enhance their reparative properties.MethodsTo evaluate this, we isolated Exo from db+ and db/db EPCs and compared their functions in terms of cell survival and angiogenic capacity in vitro. Further, we injected both db+ and db/db EPC exosomes in db+ mouse models of MI and compared their repair ability in vivo.ResultsWe report that, db+ EPC-exosomes (Exo) transplantation post-MI significantly improved db+ Exo-mediated post-infarct repair, neovascularization and LV functions. Whereas transplantation of db/db EPC-exosomes worsened heart function. Our in vitro studies revealed that db+ EPC-Exo treatment enhanced tube formation and inhibited apoptosis of human umbilical vein endothelial cells; whereas db/db EPC-Exo exhibited opposite effects, suggesting that reparative capacity of db/db EPC-Exo is impaired in Exo derived from db/db EPCs. Interestingly our microarray experiments revealed that, human CD34+ cells subjected to hyperglycemic conditions and Exo isolated from db/db mice showed elevated basal levels of miR-142 compared to control. Also functional deficiencies exhibited by db/db exosomes was partially rescued by miR-142 knockdown in db/db EPC-Exo. Knockdown of miR-142 in Exo derived from db/db EPCs enhanced endothelial cell functions in vitro.ConclusionsTaken together, our studies for the first time suggest that, modulation of miR-142 in db/db-EPC-exo can enhance its functional benefits and ultimately promote better cardiac repair.