Abstract
Rationale:
Established animal models of limb and tissue regeneration with re-vascularization demonstrate a critical dependence on concurrent reinnervation by the peripheral nervous system.
Objective:
Considering the significant abundance of autonomic nerves in the mammalian heart we tested the hypothesis that reinnervation is required for neonatal mouse cardiac regeneration.
Methods and Results:
Crossing Wnt1:cre transgenic mice with a double-tandem (td) tomato reporter strain identifies all neural crest-derived cell lineages including the peripheral autonomic nerves in the heart. Whole mount epi-fluorescence microscopy facilitated the clear resolution of subepicardial autonomic nerves in the mouse ventricles providing unprecedented detail of the subepicardial neuroanatomy of the mouse heart. Sympathetic nerve bundles envelop the entire heart and extend to the tip of the ventricular apex. Our data demonstrate that during regeneration of the resected ventricular apex of the neonatal mouse heart, sympathetic nerves fibers undergo concurrent re-growth into the injury site resulting in complete sympathetic reinnervation of the regenerated tissue. Sympathectomy of the heart, induced by administration of 6-OHDA, was sufficient to block innate cardiac regeneration in the neonatal mouse.
Conclusions:
We report that the innate ability of the neonatal mouse heart to undergo regeneration in response to injury is dependent on sympathetic innervation of the ventricular myocardium. Ablation of post-ganglionic sympathetic nerves blocks the innate regenerative capacity of neonatal mouse hearts suggesting that sympathetic reinnervation is critical for ventricular regeneration. This finding has significant implications for adult regeneration following myocardial infarction where nerve growth is hindered by age related influences and scar tissue.