Cargando…

Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction

Exosomes (Exo) secreted from hypoxia-conditioned bone marrow mesenchymal stem cells (BM-MSCs) were found to be protective for ischemic disease. However, the role of exosomal miRNA in the protective effect of hypoxia-conditioned BM-MSCs-derived Exo (Hypo-Exo) remains largely uncharacterized and the p...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhu, Ling-Ping, Tian, Tian, Wang, Jun-Yao, He, Jing-Ni, Chen, Tong, Pan, Miao, Xu, Li, Zhang, Hui-xin, Qiu, Xue-Ting, Li, Chuan-Chang, Wang, Kang-Kai, Shen, Hong, Zhang, Guo-Gang, Bai, Yong-Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299684/
https://www.ncbi.nlm.nih.gov/pubmed/30613290
http://dx.doi.org/10.7150/thno.28021
_version_ 1783381538866462720
author Zhu, Ling-Ping
Tian, Tian
Wang, Jun-Yao
He, Jing-Ni
Chen, Tong
Pan, Miao
Xu, Li
Zhang, Hui-xin
Qiu, Xue-Ting
Li, Chuan-Chang
Wang, Kang-Kai
Shen, Hong
Zhang, Guo-Gang
Bai, Yong-Ping
author_facet Zhu, Ling-Ping
Tian, Tian
Wang, Jun-Yao
He, Jing-Ni
Chen, Tong
Pan, Miao
Xu, Li
Zhang, Hui-xin
Qiu, Xue-Ting
Li, Chuan-Chang
Wang, Kang-Kai
Shen, Hong
Zhang, Guo-Gang
Bai, Yong-Ping
author_sort Zhu, Ling-Ping
collection PubMed
description Exosomes (Exo) secreted from hypoxia-conditioned bone marrow mesenchymal stem cells (BM-MSCs) were found to be protective for ischemic disease. However, the role of exosomal miRNA in the protective effect of hypoxia-conditioned BM-MSCs-derived Exo (Hypo-Exo) remains largely uncharacterized and the poor specificity of tissue targeting of Exo limits their clinical applications. Therefore, the objective of this study was to examine the effect of miRNA in Hypo-Exo on the repair of ischemic myocardium and its underlying mechanisms. We further developed modified Hypo-Exo with high specificity to the myocardium and evaluate its therapeutic effects. Methods: Murine BM-MSCs were subjected to hypoxia or normoxia culture and Exo were subsequently collected. Hypo-Exo or normoxia-conditioned BM-MSC-derived Exo (Nor-Exo) were administered to mice with permanent condition of myocardial infarction (MI). After 28 days, to evaluate the therapeutic effects of Hypo-Exo, infarction area and cardio output in Hypo-Exo and Nor-Exo treated MI mice were compared through Masson's trichrome staining and echocardiography respectively. We utilized the miRNA array to identify the significantly differentially expressed miRNAs between Nor-Exo and Hypo-Exo. One of the most enriched miRNA in Hypo-Exo was knockdown by applying antimiR in Hypoxia-conditioned BM-MSCs. Then we performed intramyocardial injection of candidate miRNA-knockdown-Hypo-Exo in a murine MI model, changes in the candidate miRNA's targets expression of cardiomyocytes and the cardiac function were characterized. We conjugated Hypo-Exo with an ischemic myocardium-targeted (IMT) peptide by bio-orthogonal chemistry, and tested its targeting specificity and therapeutic efficiency via systemic administration in the MI mice. Results: The miRNA array revealed significant enrichment of miR-125b-5p in Hypo-Exo compared with Nor-Exo. Administration of miR-125b knockdown Hypo-Exo significantly increased the infarction area and suppressed cardiomyocyte survival post-MI. Mechanistically, miR-125b knockdown Hypo-Exo lost the capability to suppress the expression of the proapoptotic genes p53 and BAK1 in cardiomyocytes. Intravenous administration of IMT-conjugated Hypo-Exo (IMT-Exo) showed specific targeting to the ischemic lesions in the injured heart and exerted a marked cardioprotective function post-MI. Conclusion: Our results illustrate a new mechanism by which Hypo-Exo-derived miR125b-5p facilitates ischemic cardiac repair by ameliorating cardiomyocyte apoptosis. Furthermore, our IMT- Exo may serve as a novel drug carrier that enhances the specificity of drug delivery for ischemic disease.
format Online
Article
Text
id pubmed-6299684
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Ivyspring International Publisher
record_format MEDLINE/PubMed
spelling pubmed-62996842019-01-04 Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction Zhu, Ling-Ping Tian, Tian Wang, Jun-Yao He, Jing-Ni Chen, Tong Pan, Miao Xu, Li Zhang, Hui-xin Qiu, Xue-Ting Li, Chuan-Chang Wang, Kang-Kai Shen, Hong Zhang, Guo-Gang Bai, Yong-Ping Theranostics Research Paper Exosomes (Exo) secreted from hypoxia-conditioned bone marrow mesenchymal stem cells (BM-MSCs) were found to be protective for ischemic disease. However, the role of exosomal miRNA in the protective effect of hypoxia-conditioned BM-MSCs-derived Exo (Hypo-Exo) remains largely uncharacterized and the poor specificity of tissue targeting of Exo limits their clinical applications. Therefore, the objective of this study was to examine the effect of miRNA in Hypo-Exo on the repair of ischemic myocardium and its underlying mechanisms. We further developed modified Hypo-Exo with high specificity to the myocardium and evaluate its therapeutic effects. Methods: Murine BM-MSCs were subjected to hypoxia or normoxia culture and Exo were subsequently collected. Hypo-Exo or normoxia-conditioned BM-MSC-derived Exo (Nor-Exo) were administered to mice with permanent condition of myocardial infarction (MI). After 28 days, to evaluate the therapeutic effects of Hypo-Exo, infarction area and cardio output in Hypo-Exo and Nor-Exo treated MI mice were compared through Masson's trichrome staining and echocardiography respectively. We utilized the miRNA array to identify the significantly differentially expressed miRNAs between Nor-Exo and Hypo-Exo. One of the most enriched miRNA in Hypo-Exo was knockdown by applying antimiR in Hypoxia-conditioned BM-MSCs. Then we performed intramyocardial injection of candidate miRNA-knockdown-Hypo-Exo in a murine MI model, changes in the candidate miRNA's targets expression of cardiomyocytes and the cardiac function were characterized. We conjugated Hypo-Exo with an ischemic myocardium-targeted (IMT) peptide by bio-orthogonal chemistry, and tested its targeting specificity and therapeutic efficiency via systemic administration in the MI mice. Results: The miRNA array revealed significant enrichment of miR-125b-5p in Hypo-Exo compared with Nor-Exo. Administration of miR-125b knockdown Hypo-Exo significantly increased the infarction area and suppressed cardiomyocyte survival post-MI. Mechanistically, miR-125b knockdown Hypo-Exo lost the capability to suppress the expression of the proapoptotic genes p53 and BAK1 in cardiomyocytes. Intravenous administration of IMT-conjugated Hypo-Exo (IMT-Exo) showed specific targeting to the ischemic lesions in the injured heart and exerted a marked cardioprotective function post-MI. Conclusion: Our results illustrate a new mechanism by which Hypo-Exo-derived miR125b-5p facilitates ischemic cardiac repair by ameliorating cardiomyocyte apoptosis. Furthermore, our IMT- Exo may serve as a novel drug carrier that enhances the specificity of drug delivery for ischemic disease. Ivyspring International Publisher 2018-11-29 /pmc/articles/PMC6299684/ /pubmed/30613290 http://dx.doi.org/10.7150/thno.28021 Text en © Ivyspring International Publisher This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Zhu, Ling-Ping
Tian, Tian
Wang, Jun-Yao
He, Jing-Ni
Chen, Tong
Pan, Miao
Xu, Li
Zhang, Hui-xin
Qiu, Xue-Ting
Li, Chuan-Chang
Wang, Kang-Kai
Shen, Hong
Zhang, Guo-Gang
Bai, Yong-Ping
Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction
title Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction
title_full Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction
title_fullStr Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction
title_full_unstemmed Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction
title_short Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction
title_sort hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through mir-125b-mediated prevention of cell death in myocardial infarction
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299684/
https://www.ncbi.nlm.nih.gov/pubmed/30613290
http://dx.doi.org/10.7150/thno.28021
work_keys_str_mv AT zhulingping hypoxiaelicitedmesenchymalstemcellderivedexosomesfacilitatescardiacrepairthroughmir125bmediatedpreventionofcelldeathinmyocardialinfarction
AT tiantian hypoxiaelicitedmesenchymalstemcellderivedexosomesfacilitatescardiacrepairthroughmir125bmediatedpreventionofcelldeathinmyocardialinfarction
AT wangjunyao hypoxiaelicitedmesenchymalstemcellderivedexosomesfacilitatescardiacrepairthroughmir125bmediatedpreventionofcelldeathinmyocardialinfarction
AT hejingni hypoxiaelicitedmesenchymalstemcellderivedexosomesfacilitatescardiacrepairthroughmir125bmediatedpreventionofcelldeathinmyocardialinfarction
AT chentong hypoxiaelicitedmesenchymalstemcellderivedexosomesfacilitatescardiacrepairthroughmir125bmediatedpreventionofcelldeathinmyocardialinfarction
AT panmiao hypoxiaelicitedmesenchymalstemcellderivedexosomesfacilitatescardiacrepairthroughmir125bmediatedpreventionofcelldeathinmyocardialinfarction
AT xuli hypoxiaelicitedmesenchymalstemcellderivedexosomesfacilitatescardiacrepairthroughmir125bmediatedpreventionofcelldeathinmyocardialinfarction
AT zhanghuixin hypoxiaelicitedmesenchymalstemcellderivedexosomesfacilitatescardiacrepairthroughmir125bmediatedpreventionofcelldeathinmyocardialinfarction
AT qiuxueting hypoxiaelicitedmesenchymalstemcellderivedexosomesfacilitatescardiacrepairthroughmir125bmediatedpreventionofcelldeathinmyocardialinfarction
AT lichuanchang hypoxiaelicitedmesenchymalstemcellderivedexosomesfacilitatescardiacrepairthroughmir125bmediatedpreventionofcelldeathinmyocardialinfarction
AT wangkangkai hypoxiaelicitedmesenchymalstemcellderivedexosomesfacilitatescardiacrepairthroughmir125bmediatedpreventionofcelldeathinmyocardialinfarction
AT shenhong hypoxiaelicitedmesenchymalstemcellderivedexosomesfacilitatescardiacrepairthroughmir125bmediatedpreventionofcelldeathinmyocardialinfarction
AT zhangguogang hypoxiaelicitedmesenchymalstemcellderivedexosomesfacilitatescardiacrepairthroughmir125bmediatedpreventionofcelldeathinmyocardialinfarction
AT baiyongping hypoxiaelicitedmesenchymalstemcellderivedexosomesfacilitatescardiacrepairthroughmir125bmediatedpreventionofcelldeathinmyocardialinfarction