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
- Cited 9
- Views 4,584
- Annotations
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.
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
-
- 4,584
- Page views
-
- 922
- Downloads
-
- 9
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.
Download links
Downloads (link to download the article as PDF)
Download citations (links to download the citations from this article in formats compatible with various reference manager tools)
Open citations (links to open the citations from this article in various online reference manager services)
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
Following testicular spermatogenesis, mammalian sperm continue to mature in a long epithelial tube known as the epididymis, which plays key roles in remodeling sperm protein, lipid, and RNA composition. To understand the roles for the epididymis in reproductive biology, we generated a single-cell atlas of the murine epididymis and vas deferens. We recovered key epithelial cell types including principal cells, clear cells, and basal cells, along with associated support cells that include fibroblasts, smooth muscle, macrophages and other immune cells. Moreover, our data illuminate extensive regional specialization of principal cell populations across the length of the epididymis. In addition to region-specific specialization of principal cells, we find evidence for functionally specialized subpopulations of stromal cells, and, most notably, two distinct populations of clear cells. Our dataset extends on existing knowledge of epididymal biology, and provides a wealth of information on potential regulatory and signaling factors that bear future investigation.
