ZFIN ID: ZDB-PUB-191226-13
Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart
Honkoop, H., de Bakker, D.E., Aharonov, A., Kruse, F., Shakked, A., Nguyen, P.D., de Heus, C., Garric, L., Muraro, M.J., Shoffner, A., Tessadori, F., Peterson, J.C., Noort, W., Bertozzi, A., Weidinger, G., Posthuma, G., Grun, D., van der Laarse, W.J., Klumperman, J., Jaspers, R.T., Poss, K.D., van Oudenaarden, A., Tzahor, E., Bakkers, J.
Date: 2019
Source: eLIFE   8: (Journal)
Registered Authors: Bakkers, Jeroen, Poss, Kenneth D., Weidinger, Gilbert
Keywords: developmental biology, mouse, regenerative medicine, stem cells, zebrafish
Microarrays: GEO:GSE139218
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cell Proliferation*
  • Cellular Reprogramming/genetics
  • Cellular Reprogramming/physiology*
  • Female
  • Gene Expression Regulation, Developmental
  • Genes, erbB-2/genetics
  • Genes, erbB-2/physiology
  • Glycolysis
  • Heart/embryology
  • Heart/physiology*
  • Hexokinase/genetics
  • Hexokinase/metabolism
  • Male
  • Mice
  • Models, Animal
  • Myocardium/metabolism
  • Myocytes, Cardiac/cytology
  • Myocytes, Cardiac/metabolism*
  • Neuregulin-1/genetics
  • Regeneration/genetics
  • Regeneration/physiology*
  • Signal Transduction/genetics
  • Signal Transduction/physiology*
  • Single-Cell Analysis/methods*
  • Zebrafish/embryology
  • Zebrafish/growth & development*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 31868166 Full text @ Elife
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.