Graft of cardiac progenitors in a pig model of right ventricular failure triggers myocardial epimorphosis, regeneration and protection of function

Abstract

The failure of diseased adult heart to regenerate is a major burden to our societies. Besides patients with ischemia and left ventricular (LV) dysfunction, progress in pediatric surgery to repair cardiac malformations has led to a growing population of now adult congenital heart diseases (CHD) patients with right ventricular (RV) failure. In the absence of any efficient pharmacological therapy for these patients, cell therapy has turned out to be the only option to regenerate the RV myocardium. In this study, we demonstrate that the adult pig with RV failure, a model of repaired tetralogy of Fallot, has the ability of regenerative epimorphosis. Human embryonic stem cell-derived cardiac Nkx2.5+ progenitor cells were seeded in a collagen based patch to cover the whole pig failing RV. We report that these cells migrate within the myocardium while reversing the interstitial fibrosis. They then engraft and fully differentiate into fetal-like human myocytes within the myocardium. The graft triggers the reprogramming of surrounding pig myocytes into Oct4+ cells. The reprogrammed myocytes re-differentiate and proliferate around human myocytes. Altogether, our findings reveal that mammalian hearts have the ability to undergo epimorphosis, the major process of endogenous regeneration that leads to a recovery of their contractile function.