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Antioxid Redox Signal. 2019 Apr 16. doi: 10.1089/ars.2018.7688. [Epub ahead of print]

Human Embryonic Stem Cell-Derived Cardiovascular Progenitors Repair Infarcted Hearts Through Modulation of Macrophages via Activation of Signal Transducer and Activator of Transcription 6.

Author information

1
1 CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Jiao Tong University School of Medicine and Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences (CAS), Chinese Academy of Sciences, Shanghai, People's Republic of China.
2
2 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences (CAS), Beijing, China.
3
3 CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Tumor and Stem Cell, SIBS, Chinese Academy of Sciences (CAS), Shanghai, People's Republic of China.
4
4 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio.

Abstract

AIMS:

Human embryonic stem cell derived-cardiovascular progenitor cells (hESC-CVPCs) are a promising cell source for cardiac repair, while the underlying mechanisms need to be elucidated. We recently observed cardioprotective effects of human pluripotent stem cell (hPSC)-CVPCs in infarcted nonhuman primates, but their effects on inflammation during early phase of myocardial infarction (MI) and the contribution of such effect to the cardioprotection are unclear.

RESULTS:

Injection of hESC-CVPCs into acutely infarcted myocardium significantly ameliorated the functional worsening and scar formation, concomitantly with reduced inflammatory reactions and cardiomyocyte apoptosis as well as increased vascularization. Moreover, hESC-CVPCs modulated cardiac macrophages toward a reparative phenotype in the infarcted hearts, and such modulation was further confirmed in vitro using human cardiovascular progenitor cell (hCVPC)-conditioned medium (hCVPC-CdM) and highly contained interleukin (IL)-4/IL-13. Furthermore, signal transducer and activator of transcription 6 (STAT6) was activated in hCVPC-CdM- and IL-4/IL-13-treated macrophages in vitro and in hESC-CVPC-implanted MI hearts, resulting in the polarization of macrophages toward a reparative phenotype in the post-MI hearts. However, hESC-CVPC-mediated modulation on macrophages and cardioprotection were abolished in STAT6-deficient MI mice.

INNOVATION:

This is the first report about the immunoregulatory role played by hESC-CVPCs in the macrophage polarization in the infarcted hearts, its importance for the infarct repair, and the underlying signaling pathway. The findings provide new insight into the mechanism of microenvironmental regulation of stem cell-based therapy during acute MI.

CONCLUSIONS:

Implantion of hESC-CVPCs during the early phase of MI promotes infarct repair via the modulation of macrophage polarization through secreted cytokine-mediated STAT6 activation. The findings suggest a therapeutic potential by modulating macrophage polarization during acute phase of MI.

KEYWORDS:

STAT6; human cardiovascular progenitor cells; inflammation; macrophages; myocardial infarction

PMID:
30854870
DOI:
10.1089/ars.2018.7688

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