Macrophage-mediated epimorphosis in pig heart with right ventricular failure

Heart left or right ventricular failure results from either ischemic or congenital diseases, respectively, and remains a major health burden in our societies. There is thus a high demand for a regenerative therapy. Yet, the ability of the adult post-mitotic mammalian heart to self-regenerate remains largely a challenge Here, we combined cell therapy in a pig with right heart failure, cardiac physiology, single cell RNA-seq and spatial transcriptomics. We demonstrate that resident cardiac macrophages mediate a process of cardiomyocytes de-differentiation to form a blastema which produces new proliferative cardiomyocytes. Thus, a mammalian heart close to a human heart features the ability to undergo epimorphosis and to regenerate. A direct and specific target of resident macrophages holds promise to regenerate hearts, specifically in a growing population of now adult congenital heart diseases patients with right ventricular failure and left without any efficient pharmacological relieving treatment.