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

Autor: Judith Klumperman, Joshua Craiger Peterson, Willem J van der Laarse, Wendy Noort, Richard T. Jaspers, Mauro J. Muraro, Kenneth D. Poss, Eldad Tzahor, Phong D. Nguyen, Avraham Shakked, George Posthuma, Gilbert Weidinger, Alla Aharonov, Fabian Kruse, Federico Tessadori, Alexander van Oudenaarden, Alberto Bertozzi, Adam R. Shoffner, Dennis E. M. de Bakker, Hessel Honkoop, Cecilia de Heus, Laurence Garric, Dominic Grün, Jeroen Bakkers
Přispěvatelé: Physiology, ACS - Heart failure & arrhythmias, Hubrecht Institute for Developmental Biology and Stem Cell Research, AMS - Ageing and Morbidity, AMS - Fundamental Research, AMS - Restoration and Development, AMS - Sports and Work
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: eLife
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, Jaspers, R T, Poss, K D, 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
eLife, Vol 8 (2019)
eLife, 8:e50163. eLife Sciences Publications Limited
eLife, 8. eLife Sciences Publications
eLife, 8:e50163. eLife Sciences Publications
ISSN: 2050-084X
Popis: 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.
eLife digest Heart attacks are a common cause of death in the Western world. During a heart attack, oxygen levels in the affected part of the heart decrease, which causes heart muscle cells to die. In humans the dead cells are replaced by a permanent scar that stabilizes the injury but does not completely heal it. As a result, individuals have a lower quality of life after a heart attack and are more likely to die from a subsequent attack. Unlike humans, zebrafish are able to regenerate their hearts after injury: heart muscle cells close to a wound divide to produce new cells that slowly replace the scar tissue and restore normal function to the area. It remains unclear, however, what stimulates the heart muscle cells of zebrafish to start dividing. To address this question, Honkoop, de Bakker et al. used a technique called single-cell sequencing to study heart muscle cells in wounded zebrafish hearts. The experiments identified a group of heart muscle cells close to the site of the wound that multiplied to repair the damage. This group of cells had altered their metabolism compared to other heart muscle cells so that they relied on a pathway called glycolysis to produce the energy and building blocks they needed to proliferate. Blocking glycolysis impaired the ability of the heart muscle cells to divide, indicating that this switch is necessary for the heart to regenerate. Further experiments showed that a signaling cascade, which includes the molecules Nrg1 and ErbB2, induces heart muscle cells in both zebrafish and mouse hearts to switch to glycolysis and undergo division. These findings indicate that activating glycolysis in heart muscle cells may help to stimulate the heart to regenerate after a heart attack or other injury. The next step following on from this work is to develop methods to activate glycolysis and promote cell division in injured hearts.
Databáze: OpenAIRE
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