Affiliation:
1. CAS Key Laboratory of Tissue Microenvironment and Tumor Laboratory of Molecular Cardiology Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences (CAS) Shanghai 200031 P. R. China
2. State Key Laboratory of Cardiovascular Disease Fuwai Hospital National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100037 China
3. Translational Medical Center for Stem Cell Therapy, Institutes for Regenerative Medicine and Heart Failure Shanghai East Hospital Tongji University School of Medicine Shanghai 200123 China
4. Department of Cardiovascular and Thoracic Surgery Shanghai East Hospital Tongji University School of Medicine Shanghai 200120 China
5. Institute for Stem Cell and Regeneration CAS Beijing 100101 China
Abstract
AbstractMyocardial infarction (MI) causes excessive damage to the myocardium, including the epicardium. However, whether pluripotent stem cell‐derived epicardial cells (EPs) can be a therapeutic approach for infarcted hearts remains unclear. Here, the authors report that intramyocardial injection of human embryonic stem cell‐derived EPs (hEPs) at the acute phase of MI ameliorates functional worsening and scar formation in mouse hearts, concomitantly with enhanced cardiomyocyte survival, angiogenesis, and lymphangiogenesis. Mechanistically, hEPs suppress MI‐induced infiltration and cytokine‐release of inflammatory cells and promote reparative macrophage polarization. These effects are blocked by a type I interferon (IFN‐I) receptor agonist RO8191. Moreover, intelectin 1 (ITLN1), abundantly secreted by hEPs, interacts with IFN‐β and mimics the effects of hEP‐conditioned medium in suppression of IFN‐β‐stimulated responses in macrophages and promotion of reparative macrophage polarization, whereas ITLN1 downregulation in hEPs cancels beneficial effects of hEPs in anti‐inflammation, IFN‐I response inhibition, and cardiac repair. Further, similar beneficial effects of hEPs are observed in a clinically relevant porcine model of reperfused MI, with no increases in the risk of hepatic, renal, and cardiac toxicity. Collectively, this study reveals hEPs as an inflammatory modulator in promoting infarct healing via a paracrine mechanism and provides a new therapeutic approach for infarcted hearts.
Funder
National Natural Science Foundation of China
Subject
General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)