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Circulation. 2014 Sep 9;130(11 Suppl 1):S60-9. doi: 10.1161/CIRCULATIONAHA.113.007917.

Cross talk of combined gene and cell therapy in ischemic heart disease: role of exosomal microRNA transfer.

Author information

1
From the Stanford Cardiovascular Institute (S.-G.O., W.H.L., M.H., D.D., K.K., V.S.-F., J.D.G., J.C.W.); and Division of Cardiology, Department of Medicine (S.-G.O., W.H.L., K.K., V.S.-F., J.C.W.), Department of Radiology (M.H., D.D., J.C.W.), and Department of Cardiothoracic Surgery (J.D.G.), Stanford University School of Medicine, CA.
2
From the Stanford Cardiovascular Institute (S.-G.O., W.H.L., M.H., D.D., K.K., V.S.-F., J.D.G., J.C.W.); and Division of Cardiology, Department of Medicine (S.-G.O., W.H.L., K.K., V.S.-F., J.C.W.), Department of Radiology (M.H., D.D., J.C.W.), and Department of Cardiothoracic Surgery (J.D.G.), Stanford University School of Medicine, CA. joewu@stanford.edu.

Abstract

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.

KEYWORDS:

exosomes; genetic therapy; hypoxia-inducible factor-1; microRNAs; stem cells

PMID:
25200057
PMCID:
PMC4862832
DOI:
10.1161/CIRCULATIONAHA.113.007917
[Indexed for MEDLINE]
Free PMC Article

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