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 C. Peterson; Wendy Noort; Alberto Bertozzi; Gilbert Weidinger; George Posthuma; Dominic Grün; 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 C. Peterson, Wendy Noort, Alberto Bertozzi, Gilbert Weidinger, George Posthuma, Dominic Grün, Willem J. van der Laarse, Judith Klumperman, Richard T. JaspersKenneth D. Poss, Alexander van Oudenaarden, Eldad Tzahor, Jeroen Bakkers^*

^*Corresponding author for this work

Physiology

Research output: Contribution to Journal › Article › Academic › 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	e50163
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.50163
Publication status	Published - 1 Dec 2019

Funding

Funding: J.B. acknowledges support from the Netherlands Cardiovascular Research Initiative and the Dutch Heart Foundation (grants CVON2011-12 HUSTCARE and Cobra3) and ERA-CVD grant CARDIO-PRO JCT2016-40-080. L.G. was supported by an EMBO long-term fellowship. P.D.N. is supported by an EMBO Long Term Fellowship ALTF1129- (016.186.017-3). G.W. was funded by the Deutsche Forschungsgemeinschaft (SFB 1149, 01KL1704). K.D.P. acknowledges support from the American Heart Association, Foundation

Funders	Funder number
Dutch Heart Foundation	Cobra3, CVON2011-12 HUSTCARE
EMBO Long Term	ALTF1129-2015, LT001404/2017-L
EU ERA-CVD	01KL1704
Foundation
Foundation Leducq
G.W.
NWO-ZonMw Veni	016.186.017-3
Netherlands Cardiovascular Research
Netherlands CardioVascular Research Initiative
National Institutes of Health	R01 HL136182, R01 HL081674, R01 HL131319
National Cancer Institute	R15CA186017
American Heart Association
Deutsche Forschungsgemeinschaft	SFB 1149
Bundesministerium für Bildung und Forschung
EMBO

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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., J Muraro, M., Shoffner, A., Tessadori, F., Peterson, J. C., Noort, W., Bertozzi, A., Weidinger, G., Posthuma, G., Grün, 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 e50163. https://doi.org/10.7554/eLife.50163

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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 {J Muraro}, Mauro and Adam Shoffner and Federico Tessadori and Peterson, {Joshua C.} and Wendy Noort and Alberto Bertozzi and Gilbert Weidinger and George Posthuma and Dominic Gr{\"u}n 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",

year = "2019",

month = dec,

day = "1",

doi = "10.7554/eLife.50163",

language = "English",

volume = "8",

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Honkoop, H, de Bakker, DEM, Aharonov, A, Kruse, F, Shakked, A, Nguyen, PD, de Heus, C, Garric, L, J Muraro, M, Shoffner, A, Tessadori, F, Peterson, JC, Noort, W, Bertozzi, A, Weidinger, G, Posthuma, G, Grün, 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, e50163. 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 - J Muraro, Mauro

AU - Shoffner, Adam

AU - Tessadori, Federico

AU - Peterson, Joshua C.

AU - Noort, Wendy

AU - Bertozzi, Alberto

AU - Weidinger, Gilbert

AU - Posthuma, George

AU - Grün, 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

PY - 2019/12/1

Y1 - 2019/12/1

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.

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DO - 10.7554/eLife.50163

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AN - SCOPUS:85077714854

SN - 2050-084X

VL - 8

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JF - eLife

M1 - e50163

ER -

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

Abstract

Funding

UN SDGs

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