Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart

Author:

Honkoop Hessel1,de Bakker Dennis EM1,Aharonov Alla2,Kruse Fabian1,Shakked Avraham2,Nguyen Phong D1,de Heus Cecilia3,Garric Laurence1,Muraro Mauro J1,Shoffner Adam4,Tessadori Federico1,Peterson Joshua Craiger5,Noort Wendy5,Bertozzi Alberto6,Weidinger Gilbert6ORCID,Posthuma George3,Grün Dominic7,van der Laarse Willem J8,Klumperman Judith3,Jaspers Richard T5ORCID,Poss Kenneth D4,van Oudenaarden Alexander1,Tzahor Eldad2ORCID,Bakkers Jeroen19ORCID

Affiliation:

1. Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, Netherlands

2. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

3. Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands

4. Regeneration Next, Department of Cell Biology, Duke University Medical Center, Durham, United States

5. Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands

6. Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany

7. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany

8. Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, Netherlands

9. Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, 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.

Funder

ERA-CVD

Deutsche Forschungsgemeinschaft

Netherlands Heart Foundation NHS/CVON

European Molecular Biology Organization

Human Frontier Science Program

Nederlandse Organisatie voor Wetenschappelijk Onderzoek

NIH Clinical Center

ERC

Fondation Leducq Transatlantic Network of Excellence

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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