Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium

Yingjie Wang, Lan Zhang, Yongjun Li, Lijuan Chen, Xiaolong Wang, Wei Guo, Xue Zhang, Gangjian Qin, Sheng Hu He, Arthur Zimmerman, Yutao Liu, Il-man Kim, Neal Lee Weintraub, Yao Liang Tang

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

Background/objectives Induced pluripotent stem cells (iPS) exhibit enhanced survival and proliferation in ischemic tissues. However, the therapeutic application of iPS cells is limited by their tumorigenic potential. We hypothesized that iPS cells can transmit cytoprotective signals to cardiomyocytes via exosomes/microvesicles. Methods Exosomes/microvesicles secreted from mouse cardiac fibroblast (CF)-derived iPS cells (iPS-exo) were purified from conditioned medium and confirmed by electron micrograph, size distribution and zeta potential by particle tracking analyzer and protein expression of the exosome markers CD63 and Tsg101. Results We observed that exosomes are at low zeta potential, and easily aggregate. Temperature affects zeta potential (- 14 to - 15 mV at 23 °C vs - 24 mV at 37 °C). The uptake of iPS-exo protects H9C2 cells against H2O2-induced oxidative stress by inhibiting caspase 3/7 activation (P < 0.05, n = 6). Importantly, iPS-exo treatment can protect against myocardial ischemia/reperfusion (MIR) injury via intramyocardial injection into mouse ischemic myocardium before reperfusion. Furthermore, iPS-exo deliver cardioprotective miRNAs, including nanog-regulated miR-21 and HIF-1α-regulated miR-210, to H9C2 cardiomyocytes in vitro. Conclusions Exosomes/microvesicles secreted by iPS cells are very effective at transmitting cytoprotective signals to cardiomyocytes in the setting of MIR. iPS-exo thus represents novel biological nanoparticles that offer the benefits of iPS cell therapy without the risk of tumorigenicity and can potentially serve as an "off-the-shelf" therapy to rescue ischemic cardiomyocytes in conditions such as MIR.

Original languageEnglish (US)
Pages (from-to)61-69
Number of pages9
JournalInternational Journal of Cardiology
Volume192
DOIs
StatePublished - Jun 9 2015

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Exosomes
Induced Pluripotent Stem Cells
MicroRNAs
Cardiac Myocytes
Myocardium
Apoptosis
Myocardial Ischemia
Myocardial Reperfusion
Caspase 7
Myocardial Reperfusion Injury
Conditioned Culture Medium
Cell- and Tissue-Based Therapy
Reperfusion Injury
Caspase 3
Nanoparticles
Reperfusion
Oxidative Stress
Therapeutics

Keywords

  • Apoptosis
  • Exosomes/microvesicles
  • Induced pluripotent stem cells
  • Myocardial ischemia/reperfusion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. / Wang, Yingjie; Zhang, Lan; Li, Yongjun; Chen, Lijuan; Wang, Xiaolong; Guo, Wei; Zhang, Xue; Qin, Gangjian; He, Sheng Hu; Zimmerman, Arthur; Liu, Yutao; Kim, Il-man; Weintraub, Neal Lee; Tang, Yao Liang.

In: International Journal of Cardiology, Vol. 192, 09.06.2015, p. 61-69.

Research output: Contribution to journalArticle

Wang, Yingjie ; Zhang, Lan ; Li, Yongjun ; Chen, Lijuan ; Wang, Xiaolong ; Guo, Wei ; Zhang, Xue ; Qin, Gangjian ; He, Sheng Hu ; Zimmerman, Arthur ; Liu, Yutao ; Kim, Il-man ; Weintraub, Neal Lee ; Tang, Yao Liang. / Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. In: International Journal of Cardiology. 2015 ; Vol. 192. pp. 61-69.
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abstract = "Background/objectives Induced pluripotent stem cells (iPS) exhibit enhanced survival and proliferation in ischemic tissues. However, the therapeutic application of iPS cells is limited by their tumorigenic potential. We hypothesized that iPS cells can transmit cytoprotective signals to cardiomyocytes via exosomes/microvesicles. Methods Exosomes/microvesicles secreted from mouse cardiac fibroblast (CF)-derived iPS cells (iPS-exo) were purified from conditioned medium and confirmed by electron micrograph, size distribution and zeta potential by particle tracking analyzer and protein expression of the exosome markers CD63 and Tsg101. Results We observed that exosomes are at low zeta potential, and easily aggregate. Temperature affects zeta potential (- 14 to - 15 mV at 23 °C vs - 24 mV at 37 °C). The uptake of iPS-exo protects H9C2 cells against H2O2-induced oxidative stress by inhibiting caspase 3/7 activation (P < 0.05, n = 6). Importantly, iPS-exo treatment can protect against myocardial ischemia/reperfusion (MIR) injury via intramyocardial injection into mouse ischemic myocardium before reperfusion. Furthermore, iPS-exo deliver cardioprotective miRNAs, including nanog-regulated miR-21 and HIF-1α-regulated miR-210, to H9C2 cardiomyocytes in vitro. Conclusions Exosomes/microvesicles secreted by iPS cells are very effective at transmitting cytoprotective signals to cardiomyocytes in the setting of MIR. iPS-exo thus represents novel biological nanoparticles that offer the benefits of iPS cell therapy without the risk of tumorigenicity and can potentially serve as an {"}off-the-shelf{"} therapy to rescue ischemic cardiomyocytes in conditions such as MIR.",
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author = "Yingjie Wang and Lan Zhang and Yongjun Li and Lijuan Chen and Xiaolong Wang and Wei Guo and Xue Zhang and Gangjian Qin and He, {Sheng Hu} and Arthur Zimmerman and Yutao Liu and Il-man Kim and Weintraub, {Neal Lee} and Tang, {Yao Liang}",
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T1 - Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium

AU - Wang, Yingjie

AU - Zhang, Lan

AU - Li, Yongjun

AU - Chen, Lijuan

AU - Wang, Xiaolong

AU - Guo, Wei

AU - Zhang, Xue

AU - Qin, Gangjian

AU - He, Sheng Hu

AU - Zimmerman, Arthur

AU - Liu, Yutao

AU - Kim, Il-man

AU - Weintraub, Neal Lee

AU - Tang, Yao Liang

PY - 2015/6/9

Y1 - 2015/6/9

N2 - Background/objectives Induced pluripotent stem cells (iPS) exhibit enhanced survival and proliferation in ischemic tissues. However, the therapeutic application of iPS cells is limited by their tumorigenic potential. We hypothesized that iPS cells can transmit cytoprotective signals to cardiomyocytes via exosomes/microvesicles. Methods Exosomes/microvesicles secreted from mouse cardiac fibroblast (CF)-derived iPS cells (iPS-exo) were purified from conditioned medium and confirmed by electron micrograph, size distribution and zeta potential by particle tracking analyzer and protein expression of the exosome markers CD63 and Tsg101. Results We observed that exosomes are at low zeta potential, and easily aggregate. Temperature affects zeta potential (- 14 to - 15 mV at 23 °C vs - 24 mV at 37 °C). The uptake of iPS-exo protects H9C2 cells against H2O2-induced oxidative stress by inhibiting caspase 3/7 activation (P < 0.05, n = 6). Importantly, iPS-exo treatment can protect against myocardial ischemia/reperfusion (MIR) injury via intramyocardial injection into mouse ischemic myocardium before reperfusion. Furthermore, iPS-exo deliver cardioprotective miRNAs, including nanog-regulated miR-21 and HIF-1α-regulated miR-210, to H9C2 cardiomyocytes in vitro. Conclusions Exosomes/microvesicles secreted by iPS cells are very effective at transmitting cytoprotective signals to cardiomyocytes in the setting of MIR. iPS-exo thus represents novel biological nanoparticles that offer the benefits of iPS cell therapy without the risk of tumorigenicity and can potentially serve as an "off-the-shelf" therapy to rescue ischemic cardiomyocytes in conditions such as MIR.

AB - Background/objectives Induced pluripotent stem cells (iPS) exhibit enhanced survival and proliferation in ischemic tissues. However, the therapeutic application of iPS cells is limited by their tumorigenic potential. We hypothesized that iPS cells can transmit cytoprotective signals to cardiomyocytes via exosomes/microvesicles. Methods Exosomes/microvesicles secreted from mouse cardiac fibroblast (CF)-derived iPS cells (iPS-exo) were purified from conditioned medium and confirmed by electron micrograph, size distribution and zeta potential by particle tracking analyzer and protein expression of the exosome markers CD63 and Tsg101. Results We observed that exosomes are at low zeta potential, and easily aggregate. Temperature affects zeta potential (- 14 to - 15 mV at 23 °C vs - 24 mV at 37 °C). The uptake of iPS-exo protects H9C2 cells against H2O2-induced oxidative stress by inhibiting caspase 3/7 activation (P < 0.05, n = 6). Importantly, iPS-exo treatment can protect against myocardial ischemia/reperfusion (MIR) injury via intramyocardial injection into mouse ischemic myocardium before reperfusion. Furthermore, iPS-exo deliver cardioprotective miRNAs, including nanog-regulated miR-21 and HIF-1α-regulated miR-210, to H9C2 cardiomyocytes in vitro. Conclusions Exosomes/microvesicles secreted by iPS cells are very effective at transmitting cytoprotective signals to cardiomyocytes in the setting of MIR. iPS-exo thus represents novel biological nanoparticles that offer the benefits of iPS cell therapy without the risk of tumorigenicity and can potentially serve as an "off-the-shelf" therapy to rescue ischemic cardiomyocytes in conditions such as MIR.

KW - Apoptosis

KW - Exosomes/microvesicles

KW - Induced pluripotent stem cells

KW - Myocardial ischemia/reperfusion

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