PUBLICATION

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

Authors
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.
ID
ZDB-PUB-191226-13
Date
2019
Source
eLIFE   8: (Journal)
Registered Authors
Bakkers, Jeroen, Poss, Kenneth D., Weidinger, Gilbert
Keywords
developmental biology, mouse, regenerative medicine, stem cells, zebrafish
Datasets
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
Abstract
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.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes