Jane Reznick: Young at Heart: neoteny and regeneration in the naked mole-rat

Speaker: 
Jane Reznick

Title: 
Young at Heart: neoteny and regeneration in the naked mole-rat

Abstract:

Adult mammalian hearts have a very limited capacity for regeneration. Following myocardial infarction, injury is typically resolved by the formation of a collagen-rich scar, leading to adverse remodeling and progressive functional decline. We have recently established that the adult naked mole-rat represents a striking exception and can regenerate its heart after a myocardial infarction, characterized by cardiomyocyte proliferation, progressive scar resolution, and recovery of cardiac function.

We find that this regenerative capacity is associated with the retention of neotenous features in the adult naked mole-rat heart. Unlike other mammals, naked mole-rat cardiomyocytes maintain a neonatal-like state across metabolic, structural, and transcriptional levels. For example, naked mole-rat hearts do not undergo the typical postnatal switch from glycolysis to fatty acid oxidation, retain immature sarcomeric organization, and preserve a pool of renewal-competent mononucleated, diploid cardiomyocytes.

We now leverage this system to uncover mechanisms that maintain the heart in a pro-renewal, permissive state and enable a pro-regenerative program after injury, with the goal of harnessing these principles to rewire non-regenerative mammalian hearts toward regeneration. Specifically, we are defining genetic and epigenetic programs that encode a cardiomyocyte capable of re-entering the cell cycle. In parallel, we use this model to identify pro-regenerative factors that can steer mammalian hearts away from fibrosis and toward regeneration. By screening for extracellular signaling molecules selectively expressed in the naked mole-rat heart but absent in mice, we have identified a candidate factor that, when administered to adult mice following MI, reduces scar formation and stimulates cardiomyocyte proliferation.

Together, this work establishes the naked mole-rat as both a model and a discovery platform to uncover principles of cardiac regeneration, with direct implications for therapeutic strategies in human heart disease.