Abstract
Studies on cardiac progenitor cells (CPCs) and their derived exosomes therapeutic potential have demonstrated only modest improvements in cardiac function. Therefore, there is an unmet need to improve the therapeutic efficacy of CPCs and their exosomes to attain clinically relevant improvement in cardiac function. The hypothesis of this project is to assess the therapeutic potential of exosomes derived from human CPCs (hCPCs) cultured under normoxia (21% O2), physoxia (5% O2) and hypoxia (1% O2) conditions. hCPCs were characterized by immunostaining of CPC-specific markers (NKX-2.5, GATA-4, and c-kit). Cell proliferation and cell death assay was not altered under physoxia. A gene expression qPCR array (84 genes) was performed to assess the modulation of hypoxic genes under three different oxygen conditions as mentioned above. Our results demonstrated that very few hypoxia-related genes were modulated under physoxia (5 genes upregulated, 4 genes down regulated). However, several genes were modulated under hypoxia (23 genes upregulated, 9 genes downregulated). Furthermore, nanoparticle tracking analysis of the exosomes isolated from hCPCs under physoxia had a 1.6-fold increase in exosome yield when compared to normoxia and hypoxia conditions. Furthermore, tube formation assay for angiogenesis indicated that exosomes derived from hCPCs cultured under physoxia significantly increased tube formation as compared to no-exosome control, 21% O2, and 1% O2 groups. Overall, our study demonstrated the therapeutic potential of physoxic oxygen microenvironment cultured hCPCs and their derived exosomes for myocardial repair.
Highlights
Myocardial infarction (MI) is responsible for the death of one American every 40 s (Benjamin et al, 2017)
Human cardiac progenitor cells (CPCs) were cultured at each oxygen concentration for 48 h with hypoxia which was achieved in a regulated hypoxia chamber at 37◦C and 5% CO2, with humidity
The 5% O2-derived EVs had the greatest percentage wound closure, this was not statistically significant compared to 21 or 1% O2 (Figure 5B). These results indicate that human CPCs (hCPCs)-derived EVs increase endothelial cell migration, a crucial component of angiogenesis, but this was not enriched by generation of EVs under hypoxic conditions
Summary
Myocardial infarction (MI) is responsible for the death of one American every 40 s (Benjamin et al, 2017). MI is caused by a limited supply of blood and oxygen to the heart, which leads to cardiac dysfunction, fibrosis, and, heart failure. Post-MI, there is a permanent loss of cardiomyocytes and scar tissue formation that results in irreversible damage and maladaptation, Physoxia-Regulated Exosome Release and Angiogenesis which affects cardiac function (Prabhu and Frangogiannis, 2016). Existing therapies have been used to prevent additional damage to the heart muscle and reduce the risk of future MI, they only slow the progression to heart failure. Effective cardiac repair is essential to restore function of the heart following MI. Cell-based therapies to aid in cardiac tissue regeneration, such as the application of stem cells, serve to be the most promising therapeutic option today (Krishna et al, 2011; Choi et al, 2015). Optimal cell type and conditions have not yet been identified for clinically relevant repair
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