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).
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
The lateral line system enables fishes and aquatic-stage amphibians to detect local water movement via mechanosensory hair cells in neuromasts, and many species to detect weak electric fields via electroreceptors (modified hair cells) in ampullary organs. Both neuromasts and ampullary organs develop from lateral line placodes, but the molecular mechanisms underpinning ampullary organ formation are understudied relative to neuromasts. This is because the ancestral lineages of zebrafish (teleosts) and Xenopus (frogs) independently lost electroreception. We identified Bmp5 as a promising candidate via differential RNA-seq in an electroreceptive ray-finned fish, the Mississippi paddlefish (Polyodon spathula; Modrell et al., 2017, eLife 6: e24197). In an experimentally tractable relative, the sterlet sturgeon (Acipenser ruthenus), we found that Bmp5 and four other Bmp pathway genes are expressed in the developing lateral line, and that Bmp signalling is active. Furthermore, CRISPR/Cas9-mediated mutagenesis targeting Bmp5 in G0-injected sterlet embryos resulted in fewer ampullary organs. Conversely, when Bmp signalling was inhibited by DMH1 treatment shortly before the formation of ampullary organ primordia, supernumerary ampullary organs developed. These data suggest that Bmp5 promotes ampullary organ development, whereas Bmp signalling via another ligand(s) prevents their overproduction. Taken together, this demonstrates opposing roles for Bmp signalling during ampullary organ formation.
