Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell-Derived Exosomes From Pediatric Patients

• Type of Material: Article
• Authors: Udit Agarwal, Emory University; Alex George, Emory University; Srishti Bhutani, Emory University; Shohini Ghosh-Choudhary, Emory University; Joshua Maxwell, Emory University; Milton E. Brown, Emory University; Yash Mehta, Emory University; Manu Omar Platt, Emory University; Yaxuan Liang, Icahn School of Medicine; Susmita Sahoo, Icahn School of Medicine; Michael E Davis, Emory University
• Language: English
• Date: 2017-02-01
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCRESAHA.116.309935
• Title of Journal or Parent Work: Circulation Research
• ISSN: 0009-7330
• Volume: 120
• Issue: 4
• Start Page: 701
• End Page: +
• Grant/Funding Information: The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health.; This study was supported in part by the Robert P. Apkarian Integrated Electron Microscopy Core (RPAIEMC) and Emory Integrated Genomics Core, which are subsidized by the Emory College of Arts and Sciences and the Emory University School of Medicine and is one of the Emory Integrated Core Facilities.; Additional support was provided by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR000454.; This work was supported by grant HL124380 from the National Heart, Lung, and Blood Institute to M.E. Davis and M.O. Platt, as well as award T32HL007745.
• Keywords: MYOCARDIAL-INFARCTION; STEM-CELLS; TRIAL; LEFT-HEART SYNDROME; Cardiac & Cardiovascular Systems; systems biology; Life Sciences & Biomedicine; ANGIOGENESIS; exosome; MECHANISMS; Science & Technology; Hematology; PROTECTS CARDIOMYOCYTES; cardiac progenitor cells; microRNA; HYPERTROPHY; Peripheral Vascular Disease; modeling; REPAIR; Cardiovascular System & Cardiology; REGENERATION
• Research Categories: Engineering, Biomedical; Health Sciences, Medicine and Surgery

Abstract

Rationale: Studies have demonstrated that exosomes can repair cardiac tissue post-myocardial infarction and recapitulate the benefits of cellular therapy. Objective: We evaluated the role of donor age and hypoxia of human pediatric cardiac progenitor cell (CPC)-derived exosomes in a rat model of ischemia-reperfusion injury. Methods and Results: Human CPCs from the right atrial appendages from children of different ages undergoing cardiac surgery for congenital heart defects were isolated and cultured under hypoxic or normoxic conditions. Exosomes were isolated from the culture-conditioned media and delivered to athymic rats after ischemia-reperfusion injury. Echocardiography at day 3 post-myocardial infarction suggested statistically improved function in neonatal hypoxic and neonatal normoxic groups compared with saline-treated controls. At 28 days post-myocardial infarction, exosomes derived from neonatal normoxia, neonatal hypoxia, infant hypoxia, and child hypoxia significantly improved cardiac function compared with those from saline-treated controls. Staining showed decreased fibrosis and improved angiogenesis in hypoxic groups compared with controls. Finally, using sequencing data, a computational model was generated to link microRNA levels to specific outcomes. Conclusions: CPC exosomes derived from neonates improved cardiac function independent of culture oxygen levels, whereas CPC exosomes from older children were not reparative unless subjected to hypoxic conditions. Cardiac functional improvements were associated with increased angiogenesis, reduced fibrosis, and improved hypertrophy, resulting in improved cardiac function; however, mechanisms for normoxic neonatal CPC exosomes improved function independent of those mechanisms. This is the first study of its kind demonstrating that donor age and oxygen content in the microenvironment significantly alter the efficacy of human CPC-derived exosomes.