Journal article
Neurotrophin-3 contributes to benefits of human embryonic stem cell-derived cardiovascular progenitor cells against reperfused myocardial infarction
Stem cells translational medicine, Vol.10(5), pp.756-772
05/2021
DOI: 10.1002/sctm.20-0456
PMCID: 8046156
PMID: 33529481
Abstract
Acute myocardial infarction (MI) resulting from coronary ischemia is a major cause of disability and death worldwide. Transplantation of human embryonic stem cell (hESC)-derived cardiovascular progenitor cells (hCVPCs) promotes the healing of infarcted hearts by secreted factors. However, the hCVPC-secreted proteins contributing to cardiac repair remain largely unidentified. In this study, we investigated protective effects of neurotrophin (NT)-3 secreted from hCVPCs in hearts against myocardial ischemia/reperfusion (I/R) injury and explored the underlying mechanisms to determine the potential of using hCVPC products as a new therapeutic strategy. The implantation of hCVPCs into infarcted myocardium at the beginning of reperfusion following 1 hour of ischemia improved cardiac function and scar formation of mouse hearts. These beneficial effects were concomitant with reduced cardiomyocyte death and increased angiogenesis. Moreover, hCVPCs secreted a rich abundance of NT-3. The cardioreparative effect of hCVPCs in the I/R hearts was mimicked by human recombinant NT-3 (hNT-3) but canceled by NT-3 neutralizing antibody (NT-3-Ab). Furthermore, endogenous NT-3 was detected in mouse adult cardiomyocytes and its level was enhanced in I/R hearts. Adenovirus-mediated NT-3 knockdown exacerbated myocardial I/R injury. Mechanistically, hNT-3 and endogenous NT-3 inhibited I/R-induced cardiomyocyte apoptosis through activating the extracellular signal-regulated kinase (ERK) and reducing the Bim level, resulting in the cardioreparative effects of infarcted hearts together with their effects in the improvement of angiogenesis. These results demonstrate for the first time that NT-3 is a cardioprotective factor secreted by hCVPCs and exists in adult cardiomyocytes that reduces I/R-induced cardiomyocyte apoptosis via the ERK-Bim signaling pathway and promotes angiogenesis. As a cell product, NT-3 may represent as a noncell approach for the treatment of myocardial I/R injury.
Details
- Title: Subtitle
- Neurotrophin-3 contributes to benefits of human embryonic stem cell-derived cardiovascular progenitor cells against reperfused myocardial infarction
- Creators
- Wei Bi - Shanghai Jiao Tong UniversityJinxi Wang - Shanghai Institute of Nutrition and HealthYun Jiang - Shanghai Institute of Nutrition and HealthQiang Li - Shanghai Institute of Nutrition and HealthShihui Wang - Shanghai Institute of Nutrition and HealthMeilan Liu - Shanghai Jiao Tong UniversityQiao Liu - Shanghai Jiao Tong UniversityFang Li - Shanghai Institute of Nutrition and HealthChristian Paul - University of Cincinnati Medical CenterYigang Wang - University of Cincinnati Medical CenterHuang-Tian Yang - Shanghai Institute of Nutrition and Health
- Resource Type
- Journal article
- Publication Details
- Stem cells translational medicine, Vol.10(5), pp.756-772
- DOI
- 10.1002/sctm.20-0456
- PMID
- 33529481
- PMCID
- 8046156
- ISSN
- 2157-6564
- eISSN
- 2157-6580
- Grant note
- DOI: 10.13039/501100003399, name: Science and Technology Commission of Shanghai Municipality; name: Major Program of Development Fund for Shanghai Zhangjiang National Innovation Demonstration Zone; DOI: 10.13039/501100001809, name: National Natural Science Foundation of China; name: Strategic Priority Research Program of the CAS; DOI: 10.13039/501100012166, name: National Key R&D Program of China; DOI: 10.13039/501100003399, name: Science and Technology Commission of Shanghai Municipality; DOI: 10.13039/501100001809, name: National Natural Science Foundation of China
- Language
- English
- Date published
- 05/2021
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984446550302771
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