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.
Cell therapy is an emerging paradigm for the treatment of heart disease. In spite of the exciting and promising preclinical results, the benefits of cell therapy for cardiac repair in patients have been modest at best. Biomaterials-based approaches may overcome the barriers of poor differentiation and retention of transplanted cells. In this study, we prepared and tested hydrogels presenting extracellular matrix (ECM)-derived adhesion peptides as delivery vehicles for c-kit cardiac progenitor cells (CPCs). We assessed their effects on cell behavior in vitro as well as cardiac repair in rats undergoing ischemia reperfusion. Hydrogels presenting the collagen-derived GFOGER peptide induced cardiomyocyte differentiation of CPCs as demonstrated by increased expression of cardiomyocyte structural proteins. However, conditioned media obtained from GFOGER hydrogels showed lower levels of secreted reparative factors. Interestingly, following injection in rats undergoing ischemia-reperfusion, treatment with CPCs encapsulated in nonadhesive RDG-presenting hydrogels resulted in the preservation of cardiac contractility and attenuation of postinfarct remodeling whereas the adhesion peptide-presenting hydrogels did not induce any functional improvement. Retention of cells was significantly higher when delivered with nonadhesive hydrogels compared to ECM-derived peptide gels. These data suggest that factors including cell differentiation state, paracrine factors and interaction with biomaterials influence the effectiveness of biomaterials-based cell therapy. A holistic consideration of these multiple variables should be included in cell-biomaterial combination therapy designs.
Myocardial infarction (MI) is the most common cause of heart failure. Excessive production of ROS plays a key role in the pathogenesis of cardiac remodeling after MI. NADPH with NADPH oxidase (Nox)2 as the catalytic subunit is a major source of superoxide production, and expression is significantly increased in the infarcted myocardium, especially by infiltrating macrophages. While microRNAs (miRNAs) are potent regulators of gene expression and play an important role in heart disease, there still lacks efficient ways to identify miRNAs that target important pathological genes for treating MI. Thus, the overall objective was to establish a miRNA screening and delivery system for improving heart function after MI using Nox2 as a critical target. With the use of the miRNA-target screening system composed of a self-assembled cell microarray (SAMcell), three miRNAs, miR-106b, miR-148b, and miR-204, were identified that could regulate Nox2 expression and its downstream products in both human and mouse macrophages. Each of these miRNAs were encapsulated into polyketal (PK3) nanoparticles that could effectively deliver miRNAs into macrophages. Both in vitro and in vivo studies in mice confirmed that PK3-miRNAs particles could inhibit Nox2 expression and activity and significantly improve infarct size and acute cardiac function after MI. In conclusion, our results show that miR-106b, miR-148b, and miR-204 were able to improve heart function after myocardial infarction in mice by targeting Nox2 and possibly altering inflammatory cytokine production. This screening system and delivery method could have broader implications for miRNA-mediated therapeutics for cardiovascular and other diseases. NADPH oxidase (Nox)2 is a promising target for treating cardiovascular disease, but there are no specific inhibitors. Finding endogenous signals that can target Nox2 and other inflammatory molecules is of great interest. In this study, we used high-throughput screening to identify microRNAs that target Nox2 and improve cardiac function after infarction.
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