Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart
- Hubrecht Institute, Netherlands
- Weizmann Institute of Science, Israel
- University Medical Center Utrecht, Netherlands
- Duke University Medical Center, United States
- Vrije Universiteit Amsterdam, Netherlands
- Ulm University, Germany
- Max Planck Institute for Immunbiology and Epigenetics, Germany
- VU University Medical Center, Netherlands
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.
Data availability
Sequencing data have been deposited in GEO under accession code GSE139218Other data generated during this study are included in the manuscript and supporting files
Article and author information
Author details
Funding
ERA-CVD (JCT2016-40-080)
- Gilbert Weidinger
- Eldad Tzahor
- Jeroen Bakkers
NIH Clinical Center (R01 HL131319)
- Kenneth D Poss
NIH Clinical Center (R01 HL136182)
- Kenneth D Poss
Deutsche Forschungsgemeinschaft (251293561)
- Gilbert Weidinger
Netherlands Heart Foundation NHS/CVON (Cobra3)
- Jeroen Bakkers
European Molecular Biology Organization (ALTF1129-2015)
- Phong D Nguyen
Human Frontier Science Program (LT001404/2017-L)
- Phong D Nguyen
Dutch Research Council (016.186.017-3)
- Phong D Nguyen
Deutsche Forschungsgemeinschaft (316249678)
- Gilbert Weidinger
Deutsche Forschungsgemeinschaft (414077062)
- Gilbert Weidinger
NIH Clinical Center (RO1 HL081674)
- Kenneth D Poss
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were conducted in accordance with the ethical guidelines. Animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the Royal Dutch Academy of Sciences (AVD801002016404), the state of Baden-Württemberg and the animal protection representative of Ulm University (Tierversuch 1352), Duke University (A057-18-02) and the Weizmann Institute (13240419-3).
Reviewing Editor
- Marianne E Bronner, California Institute of Technology, United States
Version history
- Received: July 12, 2019
- Accepted: December 4, 2019
- Accepted Manuscript published: December 23, 2019 (version 1)
- Version of Record published: February 4, 2020 (version 2)
Copyright
© 2019, Honkoop et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart
eLife 8:e50163.
https://doi.org/10.7554/eLife.50163
Further reading
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- Developmental Biology
Experiments in zebrafish have shed new light on the relationship between development and regeneration in the heart.
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- Developmental Biology
A growing body of evidence suggests that cell division and basement membrane invasion are mutually exclusive cellular behaviors. How cells switch between proliferative and invasive states is not well understood. Here, we investigated this dichotomy in vivo by examining two cell types in the developing Caenorhabditis elegans somatic gonad that derive from equipotent progenitors, but exhibit distinct cell behaviors: the post-mitotic, invasive anchor cell and the neighboring proliferative, non-invasive ventral uterine (VU) cells. We show that the fates of these cells post-specification are more plastic than previously appreciated and that levels of NHR-67 are important for discriminating between invasive and proliferative behavior. Transcription of NHR-67 is downregulated following post-translational degradation of its direct upstream regulator, HLH-2 (E/Daughterless) in VU cells. In the nuclei of VU cells, residual NHR-67 protein is compartmentalized into discrete punctae that are dynamic over the cell cycle and exhibit liquid-like properties. By screening for proteins that colocalize with NHR-67 punctae, we identified new regulators of uterine cell fate maintenance: homologs of the transcriptional co-repressor Groucho (UNC-37 and LSY-22), as well as the TCF/LEF homolog POP-1. We propose a model in which the association of NHR-67 with the Groucho/TCF complex suppresses the default invasive state in non-invasive cells, which complements transcriptional regulation to add robustness to the proliferative-invasive cellular switch in vivo.
