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
  • Gene Expression Regulation, Developmental
  • Neuregulin-1/genetics
  • Animals
  • Male
  • Cellular Reprogramming/genetics
  • Cellular Reprogramming/physiology*
  • Hexokinase/genetics
  • Hexokinase/metabolism
  • Zebrafish/embryology
  • Zebrafish/growth & development*
  • Signal Transduction/genetics
  • Signal Transduction/physiology*
  • Mice
  • Heart/embryology
  • Heart/physiology*
  • Myocardium/metabolism
  • Genes, erbB-2/genetics
  • Genes, erbB-2/physiology
  • Female
  • Glycolysis
  • Regeneration/genetics
  • Regeneration/physiology*
  • Myocytes, Cardiac/cytology
  • Myocytes, Cardiac/metabolism*
  • Models, Animal
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Cell Proliferation*
  • Animals, Genetically Modified
  • Single-Cell Analysis/methods*
(all 30)
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
Figure Gallery (15 images) / 2
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ae1TgTransgenic Insertion
    hu8889TgTransgenic Insertion
      pd10TgTransgenic Insertion
        pd107TgTransgenic Insertion
          s879TgTransgenic Insertion
            sh144TgTransgenic Insertion
              twu34TgTransgenic Insertion
                1 - 7 of 7
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                Human Disease / Model
                No data available
                Sequence Targeting Reagents
                No data available
                Fish
                No data available
                Antibodies
                Name Type Antigen Genes Isotypes Host Organism
                Ab1-mef2polyclonal
                  		IgGRabbit
                  Ab2-pcnamonoclonalIgG2aMouse
                  1 - 2 of 2
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                  Orthology
                  No data available
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  CitrineEFGCitrine
                  CreEFGCre
                  DsRedEFGDsRed
                  EGFPEFGEGFP
                  GFPEFGGFP
                  TagBFPEFGTagBFP
                  1 - 6 of 6
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                  Mapping
                  No data available
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                  Citation
                  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. (2019) Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart. eLIFE. 8:.