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
Publication 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.
Metrics
-
- 9,660
- Page views
-
- 1,409
- Downloads
-
- 76
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
-
- Developmental Biology
Experiments in zebrafish have shed new light on the relationship between development and regeneration in the heart.
-
- Developmental Biology
Codon usage bias has long been appreciated to influence protein production. Yet, relatively few studies have analyzed the impacts of codon usage on tissue-specific mRNA and protein expression. Here, we use codon-modified reporters to perform an organism-wide screen in Drosophila melanogaster for distinct tissue responses to codon usage bias. These reporters reveal a cliff-like decline of protein expression near the limit of rare codon usage in endogenously expressed Drosophila genes. Near the edge of this limit, however, we find the testis and brain are uniquely capable of expressing rare codon-enriched reporters. We define a new metric of tissue-specific codon usage, the tissue-apparent Codon Adaptation Index (taCAI), to reveal a conserved enrichment for rare codon usage in the endogenously expressed genes of both Drosophila and human testis. We further demonstrate a role for rare codons in an evolutionarily young testis-specific gene, RpL10Aa. Optimizing RpL10Aa codons disrupts female fertility. Our work highlights distinct responses to rarely used codons in select tissues, revealing a critical role for codon bias in tissue biology.
