Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart

Hessel Honkoop; Dennis EM de Bakker; Alla Aharonov; Fabian Kruse; Avraham Shakked; Phong D Nguyen; Cecilia de Heus; Laurence Garric; Mauro J Muraro; Adam Shoffner; Federico Tessadori; Joshua Craiger Peterson; Wendy Noort; Alberto Bertozzi; Gilbert Weidinger; George Posthuma; Dominic Grün; Willem J van der Laarse; Judith Klumperman; Richard T Jaspers; Kenneth D Poss; Alexander van Oudenaarden; Eldad Tzahor; Jeroen Bakkers

Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart

2019

While the heart regenerates poorly in mammals, efficient heart regeneration occurs in zebrafish. Studies in zebrafish have resulted in a model in which preexisting cardiomyocytes dedifferentiate and reinitiate proliferation to replace the lost myocardium. To identify which processes occur in proliferating cardiomyocytes we have used a single-cell RNA-sequencing approach. We uncovered that proliferating border zone cardiomyocytes have very distinct transcriptomes compared to the nonproliferating remote cardiomyocytes and that they resemble embryonic cardiomyocytes. Moreover, these cells have reduced expression of mitochondrial genes and reduced mitochondrial activity, while glycolysis gene expression and glucose uptake are increased, indicative for metabolic reprogramming. Furthermore, we find that the metabolic reprogramming of border zone cardiomyocytes is induced by Nrg1/ErbB2 signaling and is important for their proliferation. This mechanism is conserved in murine hearts in which cardiomyocyte proliferation is induced by activating ErbB2 signaling. Together these results demonstrate that glycolysis regulates cardiomyocyte proliferation during heart regeneration.

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