Participation of ventricular trabeculae in neonatal cardiac regeneration leads to ectopic recruitment of Purkinje-like cells

Unlike adult mammals, newborn mice are able to regenerate a functional heart after myocardial infarction. However, the precise origin of the newly formed cardiomyocytes and whether the distal part of the conduction system - the Purkinje Fiber (PF) network - is properly formed in regenerated hearts remains unclear. PFs, as well as subendocardial contractile cardiomyocytes, are derived from trabeculae, transient myocardial ridges on the inner ventricular surface. Here, using Connexin40-driven genetic tracing, we uncovered a substantial participation of the trabecular lineage in myocardial regeneration through dedifferentiation and proliferation. Concomitantly, regeneration disrupted PF network maturation, resulting in permanent PF hyperplasia and impaired ventricular conduction. Proliferation assays, genetic impairment of PF recruitment, lineage tracing and clonal analysis revealed that PF network hyperplasia results from excessive recruitment of PFs due to increased trabecular fate plasticity. These data identify PF network hyperplasia as a cost of the participation of trabeculae in myocardium regeneration.