Cellular therapy for chronic heart failure: a key role for epicardial fibronectin

Abstract

Myocardial infarction (MI) results in permanent cardiomyocyte loss, frequently leading to heart failure, with a 50% 5-year mortality. At subacute time points following MI, animal studies have shown ‘remuscularization’ of the damaged heart with human embryonic stem cell (hESC)-derived cardiomyocytes. Recently, outcomes were improved by co-delivering hESC-derived epicardium. Clinically, the main challenge remains chronic heart failure. However, hESC-cardiomyocytes alone, in the chronically infarcted heart, have shown no benefit. Here, we show that both species-matched cellular therapy and combination therapy with hESC-epicardium could attenuate cardiac dysfunction in the chronically failing heart, underpinned by sizeable cardiac grafts, cardiomyocyte proliferation and maturation, together with a host-derived vascular supply. Notably, hESC-epicardium’s augmentation of cardiomyocyte maturation within 3D-engineered heart tissues in vitro appeared to be underpinned by epicardial-secreted fibronectin. Thus, hESC-combination cell therapy holds clinical promise for ‘remuscularising’ chronically infarcted hearts.