Abstract 16340: Experimental, Systems and Computational Approaches to Understand the Microrna-Mediated Reparative Potential of Cardiac Progenitor Cell-Derived Exosomes From Pediatric Patients
Exosomes have shown a great potential in improving cardiac function post myocardial infarction (MI). Recently, cardiac progenitor cells (CPCs) derived exosomes have shown promising results in myocardial healing post MI. Here we demonstrate novel strategies to improve the efficacy of pediatric CPCs derived exosomes in myocardial healing post Ischemia-reperfusion (IR) injury by studying the role of donor CPCs age and hypoxic environment, and used computational modeling to predict potential microRNA mediated mechanisms. C-kit positive human CPCs from the right atrial appendage of the children undergoing heart surgeries for congenital heart defects were isolated, cultured and then subjected to hypoxia and normoxia. Groups were created based upon the age of child - Neonate (Day1 - 1month), Infant (1month-1year) and Child (1year- 5years). Isolated exosomes were delivered to athymic rats following IR injury. 2D Echo at day 3 post IR suggested improved function in neonatal hypoxic and normoxic groups compared to controls (P<0.05). Interestingly, at 28 days post IR, exosomes derived from neonatal normoxia, neonatal hypoxia, infant hypoxia, and child hypoxia improved cardiac function compared to controls (P<0.05). Furthermore, immunostaining showed decreased fibrosis (P<0.05), improved angiogenesis (P<0.05) and improved ventricular hypertrophy (P<0.05) in hypoxic groups compared to controls. Finally, using microRNA array data, a computational model linked microRNA levels to specific outcomes predicting potential mechanisms. With this study we conclude that neonatal CPCs derived exosomes improved cardiac function independent of culture oxygen levels, while CPCs derived exosomes from older children were not reparative unless subjected to hypoxic conditions. Mechanisms are reduced fibrosis and improved angiogenesis and hypertrophy resulting in improved cardiac function; however, normoxic neonatal CPCs derived exosomes induced improved cardiac function is still an enigma. This is the first study of its kind demonstrating that donor age and oxygen content in the microenvironment significantly alter the efficacy of CPC-derived exosomes. Furthermore, computational modeling suggested potential mechanisms that need to be tested in future.
Author Disclosures: U. Agarwal: None. A. George: None. S. Ghosh-Choudhary: None. J. Maxwell: None. M. Brown: None. Y. Mehta: None. S. Bhutani: None. M. Platt: None. S. Sahoo: None. M.E. Davis: None.
- © 2016 by American Heart Association, Inc.