Cross Talk of Combined Gene and Cell Therapy in Ischemic Heart Disease Role of Exosomal MicroRNA Transfer

Article

关键词: HYPOXIA-INDUCIBLE FACTOR;    MYOCARDIAL-INFARCTION;    CARDIOPROTECTION;    ANGIOGENESIS;    TRANSPLANTATION;    ENGRAFTMENT;    METABOLISM;    VESICLES;    MEDIATE;    TARGET;   

DOI  :  10.1161/CIRCULATIONAHA.113.007917

来源: SCIE

【 摘 要 】

Background-Despite the promise shown by stem cells for restoration of cardiac function after myocardial infarction, the poor survival of transplanted cells has been a major issue. Hypoxia-inducible factor-1 (HIF1) is a transcription factor that mediates adaptive responses to ischemia. Here, we hypothesize that codelivery of cardiac progenitor cells (CPCs) with a nonviral minicircle plasmid carrying HIF1 (MC-HIF1) into the ischemic myocardium can improve the survival of transplanted CPCs. Methods and Results-After myocardial infarction, CPCs were codelivered intramyocardially into adult NOD/SCID mice with saline, MC-green fluorescent protein, or MC-HIF1 versus MC-HIF1 alone (n= 10 per group). Bioluminescence imaging demonstrated better survival when CPCs were codelivered with MC-HIF1. Importantly, echocardiography showed mice injected with CPCs+ MC-HIF1 had the highest ejection fraction 6 weeks after myocardial infarction (57.1+/-2.6%; P= 0.002) followed by MC-HIF1 alone (48.5+/-2.6%; P= 0.04), with no significant protection for CPCs+ MC-green fluorescent protein (44.8+/-3.3%; P= NS) when compared with saline control (38.7+/-3.2%). In vitro mechanistic studies confirmed that cardiac endothelial cells produced exosomes that were actively internalized by recipient CPCs. Exosomes purified from endothelial cells overexpressing HIF1 had higher contents of miR-126 and miR-210. These microRNAs activated prosurvival kinases and induced a glycolytic switch in recipient CPCs, giving them increased tolerance when subjected to in vitro hypoxic stress. Inhibiting both of these miRs blocked the protective effects of the exosomes. Conclusions-In summary, HIF1 can be used to modulate the host microenvironment for improving survival of transplanted cells. The exosomal transfer of miRs from host cells to transplanted cells represents a unique mechanism that can be potentially targeted for improving survival of transplanted cells.

【 授权许可】

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