Neurotrophin-3 contributes to benefits of human embryonic stem cell-derived cardiovascular progenitor cells against reperfused myocardial infarction

Stem cells translational medicine - Tập 10 Số 5 - Trang 756-772 - 2021
Wei Bi1, Jinxi Wang1, Yun Jiang1, Qiang Li1, Shihui Wang1, Meilan Liu1, Qiao Liu1, Fang Li1, Christian Paul2, Yigang Wang2, Huang‐Tian Yang1,3,4
1CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology Shanghai Jiao Tong University School of Medicine & Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, Shanghai, People's Republic of China
2Department of Pathology and Laboratory Medicine College of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
3Institute for Stem Cell and Regeneration, CAS, Beijing, People’s Republic of China
4Translational Medical Center for Stem Cell Therapy & Institute for Heart Failure and Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine and Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, People’s Republic of China

Tóm tắt

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.

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Stem cells translational medicine

Tập 10 Số 5

756-772

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