Human Cardiac Progenitor Cells Enhance Exosome Release and Promote Angiogenesis Under Physoxia

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% O 2), physoxia (5% O 2) and hypoxia (1% O 2) 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% O 2 , and 1% O 2 groups. Overall, our study demonstrated the therapeutic potential of physoxic oxygen microenvironment cultured hCPCs and their derived exosomes for myocardial repair.

Combination of Cardiac Progenitor Cells From the Right Atrium and Left Ventricle Exhibits Synergistic Paracrine Effects In Vitro

“…This is likely through the secretion of other angiogenic factors by LV CPCs. Previous studies have demonstrated activation of pro-angiogenic platelet endothelial cell adhesion molecule-1 43 and angiopoietin-like 4 44 in CPCs exposed to hypoxia. Although we have not measured these factors in the current study, it is logical to postulate that some of these factors could have been responsible for VEGF-independent angiogenesis in LV CPCs.…”

The effect of extracellular vesicles on the regulation of mitochondria under hypoxia

“…In addition, oxygen concentration can also determine EV release. Exosomes isolated from human cardiac progenitor cells had a significantly increase under physoxia conditions (5% O 2 ) compared with normoxia (21% O 2 ) and hypoxia (1% O 2 ) 55 .…”

Ancient Evolutionary Origin and Properties of Universally Produced Natural Exosomes Contribute to Their Therapeutic Superiority Compared to Artificial Nanoparticles

“…A useful example of the hypoxia resistance properties of some exosomes involves those produced by mesenchymal stromal cells (MSCs), which now are seen as superior for therapy compared to their parental cells [ 27 ]. Their unusual properties mean that hypoxia-resistant, MSC-derived exosomes may have an important role in the treatment of diseases featuring hypoxic tissues [ 12 ], such as in myocardial infarction [ 138 , 139 , 140 ], pulmonary hypertension [ 141 , 142 ], thrombotic diseases [ 143 ], and CNS stroke [ 144 , 145 ]. Thus, hypoxia increases the potency of MSC-derived exosomes that are, in general, healing and trophic in a variety of tissue-inflammatory pathologies, particularly acting favorably on the injured vasculature [ 146 , 147 , 148 , 149 , 150 , 151 ], such as ability to treat neonatal hypoxic injury [ 152 ] and also prevent hyperoxia-induced lung responses [ 153 ].…”