title: Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium.
abstract: OBJECTIVE
  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.affiliation: Internal Medicine of Traditional Chinese Medicine, Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Internal Medicine of Traditional Chinese Medicine, Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: wxlqy0214@163.com.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Internal Medicine of Traditional Chinese Medicine, Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.affiliation: Subei People's Hospital of Jiangsu Province, Yangzhou, Jiangsu 225001, China.
authors.forename: Sheng-hu
authors.initials: SH
authors.lastname: He
authors.affiliation: Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, Augusta, GA 30912, United States.
authors.forename: Arthur
authors.initials: A
authors.lastname: Zimmerman
authors.affiliation: Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, Augusta, GA 30912, United States.
authors.forename: Yutao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, Augusta, GA 30912, United States.
authors.forename: Il-man
authors.initials: IM
authors.lastname: Kim
authors.affiliation: Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, Augusta, GA 30912, United States.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Weintraub
authors.affiliation: Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, Augusta, GA 30912, United States. Electronic address: yaotang@gru.edu.
authors.forename: Yaoliang
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000818:Animals; D017209:Apoptosis; D055252:Cell-Derived Microparticles; D002478:Cells, Cultured; D055354:Exosomes; D005347:Fibroblasts / Q000382:microbiology; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D017202:Myocardial Ischemia / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000473:pathology*
chemical_list: D035683:MicroRNAs
keywords: Apoptosis; Exosomes/microvesicles; Induced pluripotent stem cells; Myocardial ischemia/reperfusion