Exosomes From Induced Pluripotent Stem Cell–Derived Cardiomyocytes Promote Autophagy for Myocardial Repair
Abstract
Background. Induced pluripotent stem cells and their differentiated cardiomyocytes (iCMs) have tremendous potential as patient-specific therapy for ischemic cardiomyopathy following myocardial infarctions, but difficulties in viable transplantation limit clinical translation. Exosomes secreted from iCMs (iCM-Ex) can be robustly collected in vitro and injected in lieu of live iCMs as a cell-free therapy for myocardial infarction. Methods and Results. iCM-Ex were precipitated from iCM supernatant and characterized by protein marker expression, nanoparticle tracking analysis, and functionalized nanogold transmission electron microscopy. iCM-Ex were then used in in vitro and in vivo models of ischemic injuries. Cardiac function in vivo was evaluated by left ventricular ejection fraction and myocardial viability measurements by magnetic resonance imaging. Cardioprotective mechanisms were studied by JC-1 (tetraethylbenzimidazolylcarbocyanine iodide) assay, immunohistochemistry, quantitative real-time polymerase chain reaction, transmission electron microscopy, and immunoblotting. iCM-Ex measured ≈140 nm and expressed CD63 and CD9. iCM and iCM-Ex microRNA profiles had significant overlap, indicating that exosomal content was reflective of the parent cell. Mice treated with iCM-Ex demonstrated significant cardiac improvement post–myocardial infarction, with significantly reduced apoptosis and fibrosis. In vitro iCM apoptosis was significantly reduced by hypoxia and exosome biogenesis inhibition and restored by treatment with iCM-Ex or rapamycin. Autophagosome production and autophagymore »
- Authors:
-
- Stanford Univ., CA (United States). School of Medicine, Stanford Cardiovascular Inst.
- SLAC National Accelerator Lab., Menlo Park, CA (United States). Linac Coherent Light Source (LCLS); SLAC National Accelerator Lab., Menlo Park, CA (United States). Photon Ultrafast Laser Science and Engineering Inst. (PULSE)
- Stanford Univ., CA (United States). School of Medicine
- Stanford Univ., CA (United States). Medical Center
- Publication Date:
- Research Org.:
- SLAC National Accelerator Lab., Menlo Park, CA (United States)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH)
- OSTI Identifier:
- 1617007
- Grant/Contract Number:
- AC02-76SF00515
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of the American Heart Association
- Additional Journal Information:
- Journal Volume: 9; Journal Issue: 6; Journal ID: ISSN 2047-9980
- Publisher:
- American Heart Association, Inc.
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; autophagy; exosomes; iPSC; ischemic cardiomyopathy
Citation Formats
Santoso, Michelle R., Ikeda, Gentaro, Tada, Yuko, Jung, Ji‐Hye, Vaskova, Evgeniya, Sierra, Raymond G., Gati, Cornelius, Goldstone, Andrew B., von Bornstaedt, Daniel, Shukla, Praveen, Wu, Joseph C., Wakatsuki, Soichi, Woo, Y. Joseph, and Yang, Phillip C. Exosomes From Induced Pluripotent Stem Cell–Derived Cardiomyocytes Promote Autophagy for Myocardial Repair. United States: N. p., 2020.
Web. doi:10.1161/jaha.119.014345.
Santoso, Michelle R., Ikeda, Gentaro, Tada, Yuko, Jung, Ji‐Hye, Vaskova, Evgeniya, Sierra, Raymond G., Gati, Cornelius, Goldstone, Andrew B., von Bornstaedt, Daniel, Shukla, Praveen, Wu, Joseph C., Wakatsuki, Soichi, Woo, Y. Joseph, & Yang, Phillip C. Exosomes From Induced Pluripotent Stem Cell–Derived Cardiomyocytes Promote Autophagy for Myocardial Repair. United States. https://doi.org/10.1161/jaha.119.014345
Santoso, Michelle R., Ikeda, Gentaro, Tada, Yuko, Jung, Ji‐Hye, Vaskova, Evgeniya, Sierra, Raymond G., Gati, Cornelius, Goldstone, Andrew B., von Bornstaedt, Daniel, Shukla, Praveen, Wu, Joseph C., Wakatsuki, Soichi, Woo, Y. Joseph, and Yang, Phillip C. Tue .
"Exosomes From Induced Pluripotent Stem Cell–Derived Cardiomyocytes Promote Autophagy for Myocardial Repair". United States. https://doi.org/10.1161/jaha.119.014345. https://www.osti.gov/servlets/purl/1617007.
@article{osti_1617007,
title = {Exosomes From Induced Pluripotent Stem Cell–Derived Cardiomyocytes Promote Autophagy for Myocardial Repair},
author = {Santoso, Michelle R. and Ikeda, Gentaro and Tada, Yuko and Jung, Ji‐Hye and Vaskova, Evgeniya and Sierra, Raymond G. and Gati, Cornelius and Goldstone, Andrew B. and von Bornstaedt, Daniel and Shukla, Praveen and Wu, Joseph C. and Wakatsuki, Soichi and Woo, Y. Joseph and Yang, Phillip C.},
abstractNote = {Background. Induced pluripotent stem cells and their differentiated cardiomyocytes (iCMs) have tremendous potential as patient-specific therapy for ischemic cardiomyopathy following myocardial infarctions, but difficulties in viable transplantation limit clinical translation. Exosomes secreted from iCMs (iCM-Ex) can be robustly collected in vitro and injected in lieu of live iCMs as a cell-free therapy for myocardial infarction. Methods and Results. iCM-Ex were precipitated from iCM supernatant and characterized by protein marker expression, nanoparticle tracking analysis, and functionalized nanogold transmission electron microscopy. iCM-Ex were then used in in vitro and in vivo models of ischemic injuries. Cardiac function in vivo was evaluated by left ventricular ejection fraction and myocardial viability measurements by magnetic resonance imaging. Cardioprotective mechanisms were studied by JC-1 (tetraethylbenzimidazolylcarbocyanine iodide) assay, immunohistochemistry, quantitative real-time polymerase chain reaction, transmission electron microscopy, and immunoblotting. iCM-Ex measured ≈140 nm and expressed CD63 and CD9. iCM and iCM-Ex microRNA profiles had significant overlap, indicating that exosomal content was reflective of the parent cell. Mice treated with iCM-Ex demonstrated significant cardiac improvement post–myocardial infarction, with significantly reduced apoptosis and fibrosis. In vitro iCM apoptosis was significantly reduced by hypoxia and exosome biogenesis inhibition and restored by treatment with iCM-Ex or rapamycin. Autophagosome production and autophagy flux was upregulated in iCM-Ex groups in vivo and in vitro. Conclusions. iCM-Ex improve post–myocardial infarction cardiac function by regulating autophagy in hypoxic cardiomyoytes, enabling a cell-free, patient-specific therapy for ischemic cardiomyopathy.},
doi = {10.1161/jaha.119.014345},
journal = {Journal of the American Heart Association},
number = 6,
volume = 9,
place = {United States},
year = {Tue Mar 17 00:00:00 EDT 2020},
month = {Tue Mar 17 00:00:00 EDT 2020}
}
Web of Science
Works referenced in this record:
Inhibition of autophagy by berberine enhances the survival of H9C2 myocytes following hypoxia
journal, February 2017
- Jia, Zhuyin; Lin, Lu; Huang, Shanjun
- Molecular Medicine Reports, Vol. 16, Issue 2
Size and concentration analyses of extracellular vesicles by nanoparticle tracking analysis: a variation study
journal, June 2017
- Vestad, Beate; Llorente, Alicia; Neurauter, Axl
- Journal of Extracellular Vesicles, Vol. 6, Issue 1
Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Acute Myocardial Ischemic Injury
journal, January 2015
- Zhao, Yuanyuan; Sun, Xiaoxian; Cao, Wenming
- Stem Cells International, Vol. 2015
Autophagy attenuates endothelial-to-mesenchymal transition by promoting Snail degradation in human cardiac microvascular endothelial cells
journal, September 2017
- Zou, Jin; Liu, Yanhua; Li, Bingong
- Bioscience Reports, Vol. 37, Issue 5
Autophagy: Renovation of Cells and Tissues
journal, November 2011
- Mizushima, Noboru; Komatsu, Masaaki
- Cell, Vol. 147, Issue 4
Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury
journal, February 2013
- Chen, Lijuan; Wang, Yingjie; Pan, Yaohua
- Biochemical and Biophysical Research Communications, Vol. 431, Issue 3
Impaired Autophagosome Clearance Contributes to Cardiomyocyte Death in Ischemia/Reperfusion Injury
journal, June 2012
- Ma, Xiucui; Liu, Haiyan; Foyil, Sarah R.
- Circulation, Vol. 125, Issue 25
Chikusetsu saponin IVa attenuates isoprenaline-induced myocardial fibrosis in mice through activation autophagy mediated by AMPK/mTOR/ULK1 signaling
journal, May 2019
- Wang, Luopei; Yuan, Ding; Zheng, Jie
- Phytomedicine, Vol. 58
Microfluidic Single-Cell Analysis of Transplanted Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes After Acute Myocardial Infarction
journal, August 2015
- Ong, Sang-Ging; Huber, Bruno C.; Hee Lee, Won
- Circulation, Vol. 132, Issue 8
Direct Evaluation of Myocardial Viability and Stem Cell Engraftment Demonstrates Salvage of the Injured Myocardium
journal, March 2015
- Kim, Paul J.; Mahmoudi, Morteza; Ge, Xiaohu
- Circulation Research, Vol. 116, Issue 7
Embryonic Stem Cell-Derived Microvesicles Induce Gene Expression Changes in Müller Cells of the Retina
journal, November 2012
- Katsman, Diana; Stackpole, Emma J.; Domin, Daniel R.
- PLoS ONE, Vol. 7, Issue 11
Effective isolation of exosomes with polyethylene glycol from cell culture supernatant for in-depth proteome profiling
journal, January 2016
- Weng, Yejing; Sui, Zhigang; Shan, Yichu
- The Analyst, Vol. 141, Issue 15
Exosomal miR-223 Contributes to Mesenchymal Stem Cell-Elicited Cardioprotection in Polymicrobial Sepsis
journal, September 2015
- Wang, Xiaohong; Gu, Haitao; Qin, Dongze
- Scientific Reports, Vol. 5, Issue 1
Ceramide Triggers Budding of Exosome Vesicles into Multivesicular Endosomes
journal, February 2008
- Trajkovic, K.; Hsu, C.; Chiantia, S.
- Science, Vol. 319, Issue 5867
Cardiovascular autophagy: Concepts, controversies, and perspectives
journal, October 2013
- Lavandero, Sergio; Troncoso, Rodrigo; Rothermel, Beverly A.
- Autophagy, Vol. 9, Issue 10
Homing and engraftment of progenitor cells: A prerequisite for cell therapy
journal, October 2008
- Chavakis, Emmanouil; Urbich, Carmen; Dimmeler, Stefanie
- Journal of Molecular and Cellular Cardiology, Vol. 45, Issue 4
Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors
journal, November 2007
- Takahashi, Kazutoshi; Tanabe, Koji; Ohnuki, Mari
- Cell, Vol. 131, Issue 5
Exosomes as Critical Agents of Cardiac Regeneration Triggered by Cell Therapy
journal, May 2014
- Ibrahim, Ahmed Gamal-Eldin; Cheng, Ke; Marbán, Eduardo
- Stem Cell Reports, Vol. 2, Issue 5
Embryonic Stem Cell-Derived Exosomes Promote Endogenous Repair Mechanisms and Enhance Cardiac Function Following Myocardial Infarction
journal, April 2015
- Khan, M.; Nickoloff, E.; Abramova, T.
- Circulation Research, Vol. 117, Issue 1
Autophagy: A lysosomal degradation pathway with a central role in health and disease
journal, April 2009
- Eskelinen, Eeva-Liisa; Saftig, Paul
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1793, Issue 4
Hypoxia-induced autophagy: cell death or cell survival?
journal, April 2010
- Mazure, Nathalie M.; Pouysségur, Jacques
- Current Opinion in Cell Biology, Vol. 22, Issue 2
Coptisine protects cardiomyocyte against hypoxia/reoxygenation-induced damage via inhibition of autophagy
journal, August 2017
- Wang, Yahui; Wang, Qiangli; Zhang, Lu
- Biochemical and Biophysical Research Communications, Vol. 490, Issue 2
Guidelines for the use and interpretation of assays for monitoring autophagy
journal, April 2012
- Klionsky, Daniel J.; Abdalla, Fabio C.; Abeliovich, Hagai
- Autophagy, Vol. 8, Issue 4
Nerve growth factor-induced Akt/mTOR activation protects the ischemic heart via restoring autophagic flux and attenuating ubiquitinated protein accumulation
journal, December 2016
- Wang, Zhou-Guang; Li, Hao; Huang, Yan
- Oncotarget, Vol. 8, Issue 3
The potential and challenges of using stem cells for cardiovascular repair and regeneration
journal, September 2014
- Sun, Qisi; Zhang, Zhonge; Sun, Zhongjie
- Genes & Diseases, Vol. 1, Issue 1
More Than Tiny Sacks: Stem Cell Exosomes as Cell-Free Modality for Cardiac Repair
journal, January 2016
- Kishore, Raj; Khan, Mohsin
- Circulation Research, Vol. 118, Issue 2
Exosomes Derived from Mesenchymal Stem Cells Rescue Myocardial Ischaemia/Reperfusion Injury by Inducing Cardiomyocyte Autophagy Via AMPK and Akt Pathways
journal, January 2017
- Liu, Liang; Jin, Xian; Hu, Cui-Fen
- Cellular Physiology and Biochemistry, Vol. 43, Issue 1
Human umbilical cord mesenchymal stem cells derived exosomes exert antiapoptosis effect via activating PI3K/Akt/mTOR pathway on H9C2 cells
journal, April 2019
- Liu, Hui; Sun, Xiaolu; Gong, Xuhe
- Journal of Cellular Biochemistry, Vol. 120, Issue 9
Rheb is a Critical Regulator of Autophagy During Myocardial Ischemia: Pathophysiological Implications in Obesity and Metabolic Syndrome
journal, March 2012
- Sciarretta, Sebastiano; Zhai, Peiyong; Shao, Dan
- Circulation, Vol. 125, Issue 9
Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium
journal, September 2017
- Tachibana, Atsushi; Santoso, Michelle R.; Mahmoudi, Morteza
- Circulation Research, Vol. 121, Issue 6
How to Interpret LC3 Immunoblotting
journal, November 2007
- Mizushima, Noboru; Yoshimori, Tamotsu
- Autophagy, Vol. 3, Issue 6
Effect of varying hypoxia reoxygenation times on autophagy of cardiomyocytes
journal, March 2018
- Hu, Zhao; Cai, Hong-Yan; Luo, Yun-Yan
- Acta Cirurgica Brasileira, Vol. 33, Issue 3
Myocardial Regeneration via Progenitor Cell-Derived Exosomes
journal, January 2017
- Maring, Janita A.; Beez, Christien M.; Falk, Volkmar
- Stem Cells International, Vol. 2017
Beneficial Effects of Mammalian Target of Rapamycin Inhibition on Left Ventricular Remodeling After Myocardial Infarction
journal, December 2009
- Buss, Sebastian J.; Muenz, Sebastian; Riffel, Johannes H.
- Journal of the American College of Cardiology, Vol. 54, Issue 25
Production of De Novo Cardiomyocytes: Human Pluripotent Stem Cell Differentiation and Direct Reprogramming
journal, January 2012
- Burridge, Paul W.; Keller, Gordon; Gold, Joseph D.
- Cell Stem Cell, Vol. 10, Issue 1
Neutral Sphingomyelinase 2 (nSMase2)-dependent Exosomal Transfer of Angiogenic MicroRNAs Regulate Cancer Cell Metastasis
journal, February 2013
- Kosaka, Nobuyoshi; Iguchi, Haruhisa; Hagiwara, Keitaro
- Journal of Biological Chemistry, Vol. 288, Issue 15
Accumulation of autophagosomes confers cytotoxicity
journal, July 2017
- Button, Robert W.; Roberts, Sheridan L.; Willis, Thea L.
- Journal of Biological Chemistry, Vol. 292, Issue 33
Exosomes Generated From iPSC-Derivatives: New Direction for Stem Cell Therapy in Human Heart Diseases
journal, January 2017
- Jung, Ji-Hye; Fu, Xuebin; Yang, Phillip C.
- Circulation Research, Vol. 120, Issue 2
Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells
journal, April 2011
- Mittelbrunn, María; Gutiérrez-Vázquez, Cristina; Villarroya-Beltri, Carolina
- Nature Communications, Vol. 2, Issue 1
Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury
journal, May 2010
- Lai, Ruenn Chai; Arslan, Fatih; Lee, May May
- Stem Cell Research, Vol. 4, Issue 3
NOX4 regulates autophagy during energy deprivation
journal, January 2014
- Sciarretta, Sebastiano; Volpe, Massimo; Sadoshima, Junichi
- Autophagy, Vol. 10, Issue 4