Abstract
Cell based myocardium regeneration should restore overloaded right ventricular (RV) function in grown-up congenital heart diseases. The graft of human cardiac progenitors engineered to express MLC2vGFP and differentiated from embryonic stem cells, decrease fibrosis and improve RV remodeling by a still unknown mechanism. After 5 months of an overloaded RV of a pig model of repaired Tetralogy of Fallot, a collagen patch containing 107 NKX2.5+ cardiac progenitors was applied on the epicardium of the whole RV free wall (4 treated pigs). A control group (n = 4) received a cell-free or no patch. Myocardial contractility was assessed by echocardiography using strain parameters before and 2 months after cell graft. Myocardial fibrosis was quantified by red Sirius staining and fibrosis genes QPCR analysis. The fate of progenitors was tracked by GFP and human-and cardiac specific markers. RV contractility improved in the treated group by contrast to control. Expression of collagen genes, and in turn RV fibrosis were significantly lower in treated animals. While differentiating human cardiac progenitors remained in the patch, other migrated through the fibrosis and differentiated in cardiomyocytes within the myocardium. These cells featured MLC2v+ sarcomeres and were surrounded by small pigproliferating Ki-67+ TnT+ cells as well as myocytes with fetal sarcomeres. Nfkb+ Oct4+ pig cells were also observed in the neighborhood. In vitro experiments revealed that expression of Nfkb+ in neonatal myocytes or their activation by IL6 reprogrammed them into Oct4+ cells that redifferentiated into cardiomyocytes. We propose that migration of progenitors through the fibrosis triggers a local inflammation. Immune cells secrete cytokines acting on a cardiomyocytic inflammasome at the origin of cell reprogramming. Reprogrammed cells redifferentiate into cardiomyocytes while proliferating, thus regenerating the myocardium.
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