Krüppel-like factor 1 is a core cardiomyogenic trigger in zebrafish

Ogawa, Masahito; Geng, Fan‐Suo; Humphreys, David T.; Kristianto, Esther; Sheng, Delicia Z.; Hui, Subhra Prakash; Zhang, Yuxi; Sugimoto, Kotaro; Nakayama, Maki; Zheng, Dawei; Hesselson, Daniel; Hodson, Mark P.; Bogdanović, Ozren; Kikuchi, Kazu

doi:10.1126/science.abe2762

Cited by 44 publications

(34 citation statements)

References 44 publications

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“…Recently Klf1 (Krüppel-like factor 1) has been reported to be required for heart regeneration in zebrafish stimulating epigenetic and metabolic remodeling (219).…”

Section: Transcription Factorsmentioning

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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“…Recently Klf1 (Krüppel-like factor 1) has been reported to be required for heart regeneration in zebrafish stimulating epigenetic and metabolic remodeling (219).…”

Section: Transcription Factorsmentioning

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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“…This is achieved by a process in which surviving cardiomyocytes located in a region close to the injury, also called the border zone, proliferate to restore the damaged myocardium (Jopling et al, 2010a;Kikuchi et al, 2010). Cardiomyocyte proliferation in the adult zebrafish heart can be induced by activation of Nrg1, vitamin D or Klf1 signaling and involves changes in energy metabolism (Gemberling et al, 2015;Han et al, 2019;Honkoop et al, 2019;Fukuda et al, 2020;Ogawa et al, 2021),however very little is known about cellular processes and mechanisms within proliferating adult cardiomyocytes.…”

Section: Introductionmentioning

confidence: 99%

Live imaging of adult zebrafish cardiomyocyte proliferation ex vivo

et al. 2021

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Zebrafish are excellent at regenerating their heart by reinitiating proliferation in pre-existing cardiomyocytes. Studying how zebrafish achieve this holds great potential in developing new strategies to boost mammalian heart regeneration. Nevertheless, the lack of appropriate live imaging tools for the adult zebrafish heart has limited detailed studies into the dynamics underlying cardiomyocyte proliferation. Here, we address this by developing a system in which cardiac slices of the injured zebrafish heart are cultured ex vivo for several days while retaining key regenerative characteristics including cardiomyocyte proliferation. In addition, we show that the cardiac slice culture system is compatible with live timelapse imaging and allows manipulation of regenerating cardiomyocytes with drugs that normally would have toxic effects that prevent its use. Finally, we use the cardiac slices to demonstrate that adult cardiomyocytes with fully assembled sarcomeres can partially disassemble their sarcomeres in a calpain and proteasome dependent manner to progress through nuclear division and cytokinesis. In conclusion, we have developed a cardiac slice culture system, which allows imaging of native cardiomyocyte dynamics in real time to discover cellular mechanisms during heart regeneration.

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“…This suggests that these factors gain access to these sites in BZ cardiomyocytes, but that this does not lead to enhancer activation. In this respect, the recently identified function of KLF1 in rewiring of energy metabolism enabling cardiomyocyte proliferation and regeneration may be relevant in mammals [20]. Sites with reduced accessibility, reduced H3K27ac signal, or both, were enriched for MEF2 binding sites, suggesting that loss of MEF2 interaction with DNA occurs, and that this in many cases leads to reduced enhancer activity.…”

Section: Discussionmentioning

confidence: 98%

“…These transcriptomic and epigenetic alterations can be observed up to several weeks after MI, indicating the BZ cardiomyocytes are epigenetically maintained in a metabolically inactive and dedifferentiated state. The cardiomyocytes surrounding an injury in the zebrafish heart, which initiate proliferation to regenerate the heart, similarly dedifferentiate and downregulate genes for mitochondrial function and oxidative phosphorylation [19,20]. In addition, these cardiomyocytes increase glucose uptake and induce expression of glycolysis genes, and this metabolic switch was found to be essential for their proliferation during myocardial regeneration [19,21].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic State Changes Underlie Metabolic Switch in Mouse Post-Infarction Border Zone Cardiomyocytes

Günthel

Duijvenboden

Bakker

et al. 2021

JCDD

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Myocardial infarction causes ventricular muscle loss and formation of scar tissue. The surviving myocardium in the border zone, located adjacent to the infarct, undergoes profound changes in function, structure and composition. How and to what extent these changes of border zone cardiomyocytes are regulated epigenetically is not fully understood. Here, we obtained transcriptomes of PCM-1-sorted mouse cardiomyocyte nuclei of healthy left ventricle and 7 days post myocardial infarction border zone tissue. We validated previously observed downregulation of genes involved in fatty acid metabolism, oxidative phosphorylation and mitochondrial function in border zone-derived cardiomyocytes, and observed a modest induction of genes involved in glycolysis, including Slc2a1 (Glut1) and Pfkp. To gain insight into the underlying epigenetic regulatory mechanisms, we performed H3K27ac profiling of healthy and border zone cardiomyocyte nuclei. We confirmed the switch from Mef2- to AP-1 chromatin association in border zone cardiomyocytes, and observed, in addition, an enrichment of PPAR/RXR binding motifs in the sites with reduced H3K27ac signal. We detected downregulation and accompanying epigenetic state changes at several key PPAR target genes including Ppargc1a (PGC-1a), Cpt2, Ech1, Fabpc3 and Vldrl in border zone cardiomyocytes. These data indicate that changes in epigenetic state and gene regulation underlie the maintained metabolic switch in border zone cardiomyocytes.

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Krüppel-like factor 1 is a core cardiomyogenic trigger in zebrafish

Cited by 44 publications

References 44 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

Live imaging of adult zebrafish cardiomyocyte proliferation ex vivo

Epigenetic State Changes Underlie Metabolic Switch in Mouse Post-Infarction Border Zone Cardiomyocytes

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