Deciphering the potency of ventricular trabeculae to repair the heart during cardiac regeneration in the neonatal mouse

Abstract

The mammalian heart can regenerate only during the first week of life. This window coincides with the maturation of the myocardial wall through compaction of the ventricular trabeculae, transient invaginations at the inner surface of the developing heart. Trabeculae give rise both to contractile cardiomyocytes (CM) and to the Purkinje fibers of the ventricular conductive system (VCS). Given the regenerative capacities of the neonatal mammalian heart and trabeculated fish heart, we hypothesized that ventricular trabeculae possess superior regenerative capacities than compact myocardium. Investigate the contribution of ventricular trabeculae during cardiac regeneration after neonatal myocardial infarction (MI). Neonatal MI were performed by the permanent ligation of the left coronary artery on one-day-old mice. Trabecular derivatives were genetically traced using the Connexin40 driven inducible Cre recombinase together with a conditional reporter (Cx40-CreERT2; Rosa26-YFP). Cx40 being a dynamic marker of trabeculae, recombination at fetal stage labels the whole trabeculae whereas it labels the subendocardial trabeculae – mainly committed to a conductive fate – at perinatal stages. After labeling at fetal stages, numerous trabecular-derived CM were found to participate in regeneration of the myocardium. However, they show no sign of clonal expansion nor invasion of the compact myocardial layer. Comparison of recombination pre- and post-MI shows reactivation of Cx40 in the border zone indicating a switch of these CM towards a fetal phenotype – consistent with their participation to regeneration. In parallel, VCS in border zone appears abnormally thick and unmatured. Trabeculae contribute to the regeneration of the myocardium after a neonatal MI although to similar extent than compact myocardium. While the myocardium almost fully regenerates, the VCS maturation is perturbed in a regenerative context.