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

Wei Bi; Jinxi Wang; Yun Jiang; Qiang Li; Shihui Wang; Meilan Liu; Qiao Liu; Fang Li; Christian Paul; Yigang Wang; Huang-Tian Yang

doi:10.1002/sctm.20-0456

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

Stem Cells Transl Med. 2021 May;10(5):756-772. doi: 10.1002/sctm.20-0456. Epub 2021 Feb 2.

Authors

Wei Bi¹, Jinxi Wang¹, Yun Jiang¹, Qiang Li¹, Shihui Wang¹, Meilan Liu¹, Qiao Liu¹, Fang Li¹, Christian Paul², Yigang Wang², Huang-Tian Yang^{1

3

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Affiliations

¹ CAS 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.
² Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
³ Translational 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.
⁴ Institute for Stem Cell and Regeneration, CAS, Beijing, People's Republic of China.

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.

Keywords: ERK-Bim signaling pathway; apoptosis; cardiac repair; human embryonic stem cell-derived cardiovascular progenitor cells; neurotrophin-3.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Human Embryonic Stem Cells* / cytology
Humans
Mice
Myocardial Infarction* / therapy
Myocardial Reperfusion Injury* / therapy
Myocardium
Myocytes, Cardiac* / cytology
Neurotrophin 3*

Substances

NTF3 protein, human
Neurotrophin 3