Yingjie Wang1, Lan Zhang2, Yongjun Li3, Lijuan Chen4, Xiaolong Wang5, Wei Guo1, Xue Zhang6, Gangjian Qin7, Sheng-hu He8, Arthur Zimmerman9, Yutao Liu9, Il-man Kim9, Neal L Weintraub9, Yaoliang Tang10. 1. Internal Medicine of Traditional Chinese Medicine, Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. 2. Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China. 3. Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China; Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, Augusta, GA 30912, United States. 4. Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China. 5. Internal Medicine of Traditional Chinese Medicine, Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: wxlqy0214@163.com. 6. Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China; Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, Augusta, GA 30912, United States. 7. Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States. 8. Subei People's Hospital of Jiangsu Province, Yangzhou, Jiangsu 225001, China. 9. Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, Augusta, GA 30912, United States. 10. Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, Augusta, GA 30912, United States. Electronic address: yaotang@gru.edu.
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.
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.
Authors: Christopher J Evenhuis; Rosanne M Guijt; Miroslav Macka; Philip J Marriott; Paul R Haddad Journal: Electrophoresis Date: 2006-02 Impact factor: 3.535
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