Abstract 15024: Immunomodulatory Effects of Human Embryonic Stem Cell-Derived Epicardial Cells in Myocardial Infarct Healing

Abstract

Background: Acute myocardial infarction (AMI) causes excessive myocardium damage, including epicardium. Cell therapy by implantation of human pluripotent stem cell (hPSC)-derived cardiovascular cells has been tested in the infarcted hearts of preclinical models and clinical studies. However, whether hPSC-derived epicardial cells (hEPs) can be a therapeutic approach for infarcted hearts remains unclear. AMI induces inflammatory cascades, leading to multifaceted processes of myocardial injury and healing, whereas it is unknown whether hEPs regulate immune responses, especially macrophage plasticity at the acute phase of MI. Aims: to determine whether hEP implantation promotes myocardial infarct healing and modulates inflammatory response. Results: intramyocardial injection of hEPs at the acute phase of MI ameliorated functional worsening (p<0.001 vs. MI control) and scar formation of adult male NOD-SCID mouse hearts (p<0.05 vs. MI control) at day 28 post-MI, concomitantly with enhanced cardiomyocyte survival, angiogenesis, and lymphangiogenesis (p<0.05 vs. MI control). Mechanistically, hEPs suppressed AMI-induced increases of type I interferon (IFN-I) response, infiltration and cytokine-release of inflammatory cells, and promoted polarization of reparative macrophages. These effects were blocked by a IFN-I receptor agonist RO8191 in mouse model of MI. Moreover, hEP abundantly secreted intelectin 1 (ITLN1), which interacted with IFN-β and mimicked the effects of hEP-condition medium in the suppression of IFN-β-stimulated responses in macrophages and promotion of reparative macrophage polarization. However, ITLN1 downregulation in the hEPs canceled beneficial effects of hEPs in anti-inflammation and anti-IFN-I response, and in cardiac repair of infarcted hearts. Conclusions: our resutls demonstrate the reparative effects of hEP implantations in the infarcted hearts and reveal hEPs as an inflammatory modulator in promoting infarct healing via paracrine factor-mediated cell-cell communications. These findings provide new knowledges for the functions and mechanisms of hEPs for cardiac repair and suggest a therapeutic option of hEPs for ischemic myocardial repair.