Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart
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.
Metrics
-
- 12,409
- views
-
- 1,789
- downloads
-
- 169
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
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)
Further reading
-
- Developmental Biology
Experiments in zebrafish have shed new light on the relationship between development and regeneration in the heart.
-
- Developmental Biology
- Genetics and Genomics
New developmental programs can evolve through adaptive changes to gene expression. The annelid Streblospio benedicti has a developmental dimorphism, which provides a unique intraspecific framework for understanding the earliest genetic changes that take place during developmental divergence. Using comparative RNAseq through ontogeny, we find that only a small proportion of genes are differentially expressed at any time, despite major differences in larval development and life history. These genes shift expression profiles across morphs by either turning off any expression in one morph or changing the timing or amount of gene expression. We directly connect the contributions of these mechanisms to differences in developmental processes. We examine F1 offspring – using reciprocal crosses – to determine maternal mRNA inheritance and the regulatory architecture of gene expression. These results highlight the importance of both novel gene expression and heterochronic shifts in developmental evolution, as well as the trans-acting regulatory factors in initiating divergence.