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

Hessel Honkoop; Dennis E. M. de Bakker; Alla Aharonov; Fabian Kruse; Avraham Shakked; Phong D. Nguyen; Cecilia de Heus; Laurence Garric; Mauro J. Muraro; Adam Shoffner; Federico Tessadori; Joshua Craiger Peterson; Wendy Noort; Alberto Bertozzi; Gilbert Weidinger; George Posthuma; Dominic Grun; Willem J. van der Laarse; Judith Klumperman; Richard T. Jaspers; Kenneth D. Poss; Alexander van Oudenaarden; Eldad Tzahor; Jeroen Bakkers

doi:10.7554/eLife.50163

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

Hessel Honkoop, Dennis E. M. de Bakker, Alla Aharonov, Fabian Kruse, Avraham Shakked, Phong D. Nguyen, Cecilia de Heus, Laurence Garric, Mauro J. Muraro, Adam Shoffner, Federico Tessadori, Joshua Craiger Peterson, Wendy Noort, Alberto Bertozzi, Gilbert Weidinger, George Posthuma, Dominic Grun, Willem J. van der Laarse, Judith Klumperman, Richard T. JaspersKenneth D. Poss, Alexander van Oudenaarden, Eldad Tzahor, Jeroen Bakkers

Department of Molecular Cell Biology

Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	50163
Number of pages	27
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.50163
State	Published - 23 Dec 2019

All Science Journal Classification (ASJC) codes

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

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Honkoop, H., de Bakker, D. E. M., Aharonov, A., Kruse, F., Shakked, A., Nguyen, P. D., de Heus, C., Garric, L., Muraro, M. J., Shoffner, A., Tessadori, F., Peterson, J. C., Noort, W., Bertozzi, A., Weidinger, G., Posthuma, G., Grun, D., van der Laarse, W. J., Klumperman, J., ... Bakkers, J. (2019). Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart. eLife, 8, Article 50163. https://doi.org/10.7554/eLife.50163

@article{44124fa0acc54f7a8fcf9472d1c6ba46,

title = "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.",

author = "Hessel Honkoop and {de Bakker}, {Dennis E. M.} and Alla Aharonov and Fabian Kruse and Avraham Shakked and Nguyen, {Phong D.} and {de Heus}, Cecilia and Laurence Garric and Muraro, {Mauro J.} and Adam Shoffner and Federico Tessadori and Peterson, {Joshua Craiger} and Wendy Noort and Alberto Bertozzi and Gilbert Weidinger and George Posthuma and Dominic Grun and {van der Laarse}, {Willem J.} and Judith Klumperman and Jaspers, {Richard T.} and Poss, {Kenneth D.} and {van Oudenaarden}, Alexander and Eldad Tzahor and Jeroen Bakkers",

note = "We would like to thank V Christoffels for critical reading of the manuscript and Life Science Editors for editing support. Funding ERA-CVD (JCT2016-40-080): Gilbert Weidinger, Eldad Tzahor, Jeroen Bakkers 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 Nederlandse Organisatie voor Wetenschappelijk Onderzoek (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 NIH Clinical Center (R01 HL131319): Kenneth D Poss NIH Clinical Center (R01 HL136182): Kenneth D Poss ERC (StG281289): Eldad Tzahor ERC (AdG788194): Eldad Tzahor Fondation Leducq Transatlantic Network of Excellence (15CVD03): Eldad Tzahor",

year = "2019",

month = dec,

day = "23",

doi = "10.7554/eLife.50163",

language = "الإنجليزيّة",

volume = "8",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications Ltd",

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Honkoop, H, de Bakker, DEM, Aharonov, A, Kruse, F, Shakked, A, Nguyen, PD, de Heus, C, Garric, L, Muraro, MJ, Shoffner, A, Tessadori, F, Peterson, JC, Noort, W, Bertozzi, A, Weidinger, G, Posthuma, G, Grun, D, van der Laarse, WJ, Klumperman, J, Jaspers, RT, Poss, KD, van Oudenaarden, A, Tzahor, E & Bakkers, J 2019, 'Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart', eLife, vol. 8, 50163. https://doi.org/10.7554/eLife.50163

TY - JOUR

T1 - Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart

AU - Honkoop, Hessel

AU - de Bakker, Dennis E. M.

AU - Aharonov, Alla

AU - Kruse, Fabian

AU - Shakked, Avraham

AU - Nguyen, Phong D.

AU - de Heus, Cecilia

AU - Garric, Laurence

AU - Muraro, Mauro J.

AU - Shoffner, Adam

AU - Tessadori, Federico

AU - Peterson, Joshua Craiger

AU - Noort, Wendy

AU - Bertozzi, Alberto

AU - Weidinger, Gilbert

AU - Posthuma, George

AU - Grun, Dominic

AU - van der Laarse, Willem J.

AU - Klumperman, Judith

AU - Jaspers, Richard T.

AU - Poss, Kenneth D.

AU - van Oudenaarden, Alexander

AU - Tzahor, Eldad

AU - Bakkers, Jeroen

N1 - We would like to thank V Christoffels for critical reading of the manuscript and Life Science Editors for editing support. Funding ERA-CVD (JCT2016-40-080): Gilbert Weidinger, Eldad Tzahor, Jeroen Bakkers 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 Nederlandse Organisatie voor Wetenschappelijk Onderzoek (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 NIH Clinical Center (R01 HL131319): Kenneth D Poss NIH Clinical Center (R01 HL136182): Kenneth D Poss ERC (StG281289): Eldad Tzahor ERC (AdG788194): Eldad Tzahor Fondation Leducq Transatlantic Network of Excellence (15CVD03): Eldad Tzahor

PY - 2019/12/23

Y1 - 2019/12/23

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85077714854&partnerID=8YFLogxK

U2 - 10.7554/eLife.50163

DO - 10.7554/eLife.50163

M3 - مقالة

SN - 2050-084X

VL - 8

JO - eLife

JF - eLife

M1 - 50163

ER -

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

Abstract

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