Cross talk of combined gene and cell therapy in ischemic heart disease role of exosomal MicroRNA transfer

Sang Ging Ong, Won Hee Lee, Mei Huang, Devaveena Dey, Kazuki Kodo, Veronica Sanchez-Freire, Joseph D. Gold, Joseph C. Wu

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)S60-S69
JournalCirculation
Volume130
Issue number11
DOIs
Publication statusPublished - 2014
Externally publishedYes

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Cell- and Tissue-Based Therapy
MicroRNAs
Genetic Therapy
Myocardial Ischemia
Stem Cells
Hypoxia-Inducible Factor 1
Plasmids
Exosomes
Cell Survival
Myocardial Infarction
Green Fluorescent Proteins
Endothelial Cells
Cell Hypoxia
Inbred NOD Mouse
SCID Mice
Echocardiography
Myocardium
Transcription Factors
Phosphotransferases
Ischemia

Keywords

  • Exosomes
  • Genetic therapy
  • Hypoxia-inducible factor-1
  • microRNAs
  • Stem cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Cross talk of combined gene and cell therapy in ischemic heart disease role of exosomal MicroRNA transfer. / Ong, Sang Ging; Lee, Won Hee; Huang, Mei; Dey, Devaveena; Kodo, Kazuki; Sanchez-Freire, Veronica; Gold, Joseph D.; Wu, Joseph C.

In: Circulation, Vol. 130, No. 11, 2014, p. S60-S69.

Research output: Contribution to journalArticle

Ong, SG, Lee, WH, Huang, M, Dey, D, Kodo, K, Sanchez-Freire, V, Gold, JD & Wu, JC 2014, 'Cross talk of combined gene and cell therapy in ischemic heart disease role of exosomal MicroRNA transfer', Circulation, vol. 130, no. 11, pp. S60-S69. https://doi.org/10.1161/CIRCULATIONAHA.113.007917
Ong, Sang Ging ; Lee, Won Hee ; Huang, Mei ; Dey, Devaveena ; Kodo, Kazuki ; Sanchez-Freire, Veronica ; Gold, Joseph D. ; Wu, Joseph C. / Cross talk of combined gene and cell therapy in ischemic heart disease role of exosomal MicroRNA transfer. In: Circulation. 2014 ; Vol. 130, No. 11. pp. S60-S69.
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AU - Lee, Won Hee

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AU - Dey, Devaveena

AU - Kodo, Kazuki

AU - Sanchez-Freire, Veronica

AU - Gold, Joseph D.

AU - Wu, Joseph C.

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N2 - 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.

AB - 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.

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