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

Abstract

Rationale Studies have demonstrated that exosomes can repair cardiac tissue post myocardial infarction (MI) 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 (IR) 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 following IR injury. Echocardiography at day-3 post-MI suggested statistically improved function in neonatal hypoxic and neonatal normoxic groups compared to saline-treated controls. At 28 days post-MI exosomes derived from neonatal normoxia, neonatal hypoxia, infant hypoxia, and child hypoxia significantly improved cardiac function compared to saline-treated controls. Staining showed decreased fibrosis and improved angiogenesis in hypoxic groups compared to controls. Finally, using sequencing data, a computational model was generated to link microRNA levels to specific outcomes. Conclusion CPC exosomes derived from neonates improved cardiac function independent of culture oxygen levels, while 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.

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

“…Recent advances in cellular genetic editing techniques such as CRISPR‐Cas9 could be harnessed to upregulate or augment intrinsic MSCs enzyme function before implantation in order to achieve maximal benefit. Alternatively, the growing field of exosomal/hydrogel engineering has shown growing promise as a novel, efficacious disease treatment strategy 71, 72. With increasing mechanistic insight, these treatment strategies may converge and be used to guide further studies aimed at engineering the optimal use of cells or cell components for future iterations of cell‐based therapy in MI/R injury.…”

Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia

“…Agarwal et al (38) elavuated the role of donor age and hypoxia of human pediatric CPC exosomes in a rat model of myocardial IR injury. 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.…”

Stem Cell Therapy in Heart Diseases – Cell Types, Mechanisms and Improvement Strategies

“…neovascularization, reduced apoptosis of endogenous cardiomyocytes, activation of tissue intrinsic progenitor cells or recruitment of cells beneficial for tissue repair [260,287,290]. Beside the donor´s health status, chronological age significantly influences the characteristics of the SC´s secretome and thereby affects their potential to promote myocardial recovery [291][292][293].…”