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

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

doi:10.7554/elife.50163.sa2

Cited by 5 publications

(8 citation statements)

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“…In zebrafish, proliferating cardiomyocytes in the border zone of the wounded heart, where cardiomyocyte dedifferentiation mainly occurs, switch their metabolism from oxidative phosphorylation to glycolysis, as manifested by reduced mitochondrial genes and increased glycolytic genes (60). This process was reported to be induced by Neuregulin-1/Erbb2 signaling (60). Importantly, inhibition of glycolysis after cardiac injury impairs cardiomyocyte proliferation in adult zebrafish (60).…”

Section: Energetic Metabolismmentioning

confidence: 99%

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

Bongiovanni

Sacchi

Pra

et al. 2021

Front. Cardiovasc. Med.

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Despite considerable efforts carried out to develop stem/progenitor cell-based technologies aiming at replacing and restoring the cardiac tissue following severe damages, thus far no strategies based on adult stem cell transplantation have been demonstrated to efficiently generate new cardiac muscle cells. Intriguingly, dedifferentiation, and proliferation of pre-existing cardiomyocytes and not stem cell differentiation represent the preponderant cellular mechanism by which lower vertebrates spontaneously regenerate the injured heart. Mammals can also regenerate their heart up to the early neonatal period, even in this case by activating the proliferation of endogenous cardiomyocytes. However, the mammalian cardiac regenerative potential is dramatically reduced soon after birth, when most cardiomyocytes exit from the cell cycle, undergo further maturation, and continue to grow in size. Although a slow rate of cardiomyocyte turnover has also been documented in adult mammals, both in mice and humans, this is not enough to sustain a robust regenerative process. Nevertheless, these remarkable findings opened the door to a branch of novel regenerative approaches aiming at reactivating the endogenous cardiac regenerative potential by triggering a partial dedifferentiation process and cell cycle re-entry in endogenous cardiomyocytes. Several adaptations from intrauterine to extrauterine life starting at birth and continuing in the immediate neonatal period concur to the loss of the mammalian cardiac regenerative ability. A wide range of systemic and microenvironmental factors or cell-intrinsic molecular players proved to regulate cardiomyocyte proliferation and their manipulation has been explored as a therapeutic strategy to boost cardiac function after injuries. We here review the scientific knowledge gained thus far in this novel and flourishing field of research, elucidating the key biological and molecular mechanisms whose modulation may represent a viable approach for regenerating the human damaged myocardium.

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Section: Energetic Metabolismmentioning

confidence: 99%

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

Bongiovanni

Sacchi

Pra

et al. 2021

Front. Cardiovasc. Med.

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“…Following injury, cardiomyocyte dedifferentiation and proliferation are required to regenerate the heart following injury. Interestingly, singlecell transcriptional analysis of regenerating zebrafish hearts demonstrate that proliferating border zone cardiomyocytes undergo metabolic reprogramming to glycolysis from oxidative phosphorylation following cryoinjury (15). In contrast, glycolysis inhibitors including 2-deoxyglucose and lonidamine impair cardiomyocyte proliferation and heart regeneration (15).…”

Section: Energy Metabolism and Heart Regenerationmentioning

confidence: 99%

“…Interestingly, singlecell transcriptional analysis of regenerating zebrafish hearts demonstrate that proliferating border zone cardiomyocytes undergo metabolic reprogramming to glycolysis from oxidative phosphorylation following cryoinjury (15). In contrast, glycolysis inhibitors including 2-deoxyglucose and lonidamine impair cardiomyocyte proliferation and heart regeneration (15). These results suggest that the glycolytic metabolic state mediates cardiomyocyte proliferation and regeneration following injury in zebrafish.…”

Section: Energy Metabolism and Heart Regenerationmentioning

confidence: 99%

“…In adult zebrafish, increased glycolysis has been shown to promote cardiomyocyte proliferation through increased cell cycle gene expression following injury (67). In addition, inhibition of glycolysis by 2-deoxyglucose reduced cardiomyocyte proliferation in the injured zebrafish heart (15). Thus, key components of glycolysis play an important role during cardiomyocyte proliferation and heart regeneration.…”

Section: Glucose Metabolism In Heartmentioning

confidence: 99%

“…SDH knockdown induces cell proliferation and migration in human hepatocellular carcinoma cell lines and leads to a metabolic shift to glycolysis as demonstrated by increased level of glycolytic enzymes (109). Interestingly, a recent study demonstrated that metabolic reprogramming to glycolysis promotes cardiomyocyte proliferation and heart regeneration following injury in zebrafish (15). Remarkably, SDH inhibition by malonate promotes adult cardiomyocyte proliferation, revascularization, and heart regeneration following adult myocardial infarction (110).…”

Section: Tca Cycle Metabolites In the Heartmentioning

confidence: 99%

See 2 more Smart Citations

The Role of Metabolism in Heart Failure and Regeneration

Bae

Paltzer

Mahmoud

2021

Front. Cardiovasc. Med.

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Heart failure is the leading cause of death worldwide. The inability of the adult mammalian heart to regenerate following injury results in the development of systolic heart failure. Thus, identifying novel approaches toward regenerating the adult heart has enormous therapeutic potential for adult heart failure. Mitochondrial metabolism is an essential homeostatic process for maintaining growth and survival. The emerging role of mitochondrial metabolism in controlling cell fate and function is beginning to be appreciated. Recent evidence suggests that metabolism controls biological processes including cell proliferation and differentiation, which has profound implications during development and regeneration. The regenerative potential of the mammalian heart is lost by the first week of postnatal development when cardiomyocytes exit the cell cycle and become terminally differentiated. This inability to regenerate following injury is correlated with the metabolic shift from glycolysis to fatty acid oxidation that occurs during heart maturation in the postnatal heart. Thus, understanding the mechanisms that regulate cardiac metabolism is key to unlocking metabolic interventions during development, disease, and regeneration. In this review, we will focus on the emerging role of metabolism in cardiac development and regeneration and discuss the potential of targeting metabolism for treatment of heart failure.

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Macrophages stimulate epicardial VEGFaa expression to trigger cardiomyocyte proliferation in larval zebrafish heart regeneration

Kaveh

Ross-Stewart

et al. 2021

Preprint

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Cardiac injury induces a sustained innate immune response in both zebrafish and mammals. Macrophages, highly plastic immune cells, perform a range of both beneficial and detrimental functions during mammalian cardiac repair yet their precise roles in zebrafish cardiac regeneration are not fully understood. Here we characterise cardiac regeneration in the rapidly regenerating larval zebrafish laser injury model and use macrophage ablation and macrophage-less irf8 mutants to define the requirement of macrophages for key stages of regeneration. We found macrophages to display cellular heterogeneity and plasticity in larval heart injury as in mammals. Live heartbeat-synchronised imaging and RNAseq revealed an early proinflammatory macrophage phase which then resolves to an anti-inflammatory, profibrotic phase. Macrophages are required for cardiomyocyte proliferation but not for functional or structural recovery following injury. Macrophages are specifically recruited to the epicardial-myocardial niche, triggering the expansion of the epicardium which upregulates mitogen VEGFaa. Experimental perturbation of VEGF signalling confirmed VEGFaa to be an important inducer of cardiomyocyte proliferation revealing a previously unrecognised mechanism by which macrophages aid cardiac regeneration.

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

Cited by 5 publications

References 0 publications

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

The Role of Metabolism in Heart Failure and Regeneration

Macrophages stimulate epicardial VEGFaa expression to trigger cardiomyocyte proliferation in larval zebrafish heart regeneration

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