A calcineurin–Hoxb13 axis regulates growth mode of mammalian cardiomyocytes

Nguyen, Ngoc Uyen Nhi; Canseco, Diana C.; Xiao, Feng; Nakada, Yuji; Li, Shujuan; Lam, Nicholas T.; Muralidhar, Shalini; Savla, Jainy; Hill, Joseph A.; Le, Victor; Zidan, Kareem A.; El-Feky, Hamed W.; Wang, Zhaoning; Ahmed, Mahmoud S.; Hubbi, Maimon E.; Menendez-Montes, Ivan; Moon, Jesung; Ali, Shaukat; Le, Victoria; Villalobos, Elisa; Mohamed, Magid S.; Elhelaly, Waleed M.; Thet, Suwannee; Anene-Nzelu, Chukwuemeka George; Tan, Wilson Lek Wen; Foo, Roger Sik‐Yin; Meng, Xianghong; Kanchwala, Mohammed; Xing, Chao; Roy, Jagoree; Cyert, Martha S.; Rothermel, Beverly A.; Sadek, Hesham A.

doi:10.1038/s41586-020-2228-6

Cited by 92 publications

(90 citation statements)

References 40 publications

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“…Notable was significantly decreased fibrosis with a Dach1 OE -specific pattern where damaged myocardium was restricted to an intramyocardial region and covered by surviving myocardium on both the epicardial and endocardial faces. This pattern was also evident in a recent study reporting enhanced cardiac regeneration following Meis1 and HoxB13 deletion (Uyen et al, 2020). It is tempting to speculate that vascular changes imparted by Dach1 OE preserved these myocardial domains, and that this contributed to better function and survival.…”

Section: Discussionsupporting

confidence: 58%

Dach1 extends artery networks and protects against cardiac injury

Raftrey

Williams

Coronado

et al. 2020

Preprint

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Coronary artery disease (CAD) is the leading cause of death worldwide, but there are currently no available methods to stimulate growth or regeneration of artery networks in diseased hearts. Studying how arteries are built during embryonic development could illuminate strategies for re-building these vessels in the setting of ischemic heart disease. We previously found, using loss-of-function experiments, that the transcription factor Dach1 is required for coronary artery development in mouse embryos. Here, we report that Dach1 overexpression in endothelial cells (ECs) extended coronary arteries and improved survival and heart function in adult mice following myocardial infarction (MI). Dach1 overexpression increased the length and number of arterial end branches, in both heart and retinal vasculature, by causing additional capillary ECs to differentiate into arterial ECs and contribute to growing arteries. Single-cell RNA sequencing (scRNAseq) of ECs undergoing Dach1-induced arterial specification indicated that it potentiated normal artery differentiation, rather than functioning as a master regulator of artery cell fate. ScRNAseq also showed that normal arterial differentiation is accompanied by repression of lipid metabolism genes, which were also repressed by Dach1 prior to arterialization. Together, these results demonstrate that increasing the expression level of Dach1 is a novel pathway for driving specification of artery ECs and extending arterial vessels, which could be explored as a means of increasing artery coverage to mitigate the effects of CAD.

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Section: Discussionsupporting

confidence: 58%

Dach1 extends artery networks and protects against cardiac injury

Raftrey

Williams

Coronado

et al. 2020

Preprint

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“… 7 Moreover, the synergistic effect of MEIS1 and its cofactor homeobox B13 (Hoxb13) can jointly regulate the proliferation window of cardiomyocytes after birth and the repair and regeneration of the adult heart. 118 On the contrary, Tbx20, a member of the Tbx1 subfamily of T-box (Tbx) genes, directly repressed the expression of cell cycle inhibitors p21, MEIS1 and Btg2. Overexpression of Tbx20 in adult mouse cardiomyocytes can promote cell proliferation and significantly improve heart repair after MI.…”

Section: Proliferation and Mitosis Of Pre-existing Cardiomyocytesmentioning

confidence: 99%

Regulation of cardiomyocyte fate plasticity: a key strategy for cardiac regeneration

Gong

Jiang

Загидуллин

et al. 2021

Sig Transduct Target Ther

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With the high morbidity and mortality rates, cardiovascular diseases have become one of the most concerning diseases worldwide. The heart of adult mammals can hardly regenerate naturally after injury because adult cardiomyocytes have already exited the cell cycle, which subseqently triggers cardiac remodeling and heart failure. Although a series of pharmacological treatments and surgical methods have been utilized to improve heart functions, they cannot replenish the massive loss of beating cardiomyocytes after injury. Here, we summarize the latest research progress in cardiac regeneration and heart repair through altering cardiomyocyte fate plasticity, which is emerging as an effective strategy to compensate for the loss of functional cardiomyocytes and improve the impaired heart functions. First, residual cardiomyocytes in damaged hearts re-enter the cell cycle to acquire the proliferative capacity by the modifications of cell cycle-related genes or regulation of growth-related signals. Additionally, non-cardiomyocytes such as cardiac fibroblasts, were shown to be reprogrammed into cardiomyocytes and thus favor the repair of damaged hearts. Moreover, pluripotent stem cells have been shown to transform into cardiomyocytes to promote heart healing after myocardial infarction (MI). Furthermore, in vitro and in vivo studies demonstrated that environmental oxygen, energy metabolism, extracellular factors, nerves, non-coding RNAs, etc. play the key regulatory functions in cardiac regeneration. These findings provide the theoretical basis of targeting cellular fate plasticity to induce cardiomyocyte proliferation or formation, and also provide the clues for stimulating heart repair after injury.

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“…In addition, Meis1 interacts with its co-factor Hoxb13 to cooperatively regulate cardiomyocyte proliferation and maturation. Cardiomyocyte-specific deletion of Hoxb13 defers the postnatal window of cardiac regeneration and reactivates cardiomyocyte cell cycle entry in adult heart, whereas double knockouts of Meis1 and Hoxb13 lead to widespread cardiomyocyte mitosis and improved left ventricle systolic function after myocardial infarction ( Nguyen et al, 2020 ). Recently, the combinatorial expression of four cell cycle regulators CDK1 , CDK4, cyclin B1 , and cyclin D1 was shown to be sufficient to induce cell division in post-mitotic cardiomyocytes across multiple species including mouse, rat and human ( Mohamed et al, 2018 ).…”

Section: Regulation Of Cardiomyocyte Maturation (Hypertrophy) After Bmentioning

confidence: 99%

Cardiomyocyte Proliferation and Maturation: Two Sides of the Same Coin for Heart Regeneration

Zhao

et al. 2020

Front. Cell Dev. Biol.

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In the past few decades, cardiac regeneration has been the central target for restoring the injured heart. In mammals, cardiomyocytes are terminally differentiated and rarely divide during adulthood. Embryonic and fetal cardiomyocytes undergo robust proliferation to form mature heart chambers in order to accommodate the increased workload of a systemic circulation. In contrast, postnatal cardiomyocytes stop dividing and initiate hypertrophic growth by increasing the size of the cardiomyocyte when exposed to increased workload. Extracellular and intracellular signaling pathways control embryonic cardiomyocyte proliferation and postnatal cardiac hypertrophy. Harnessing these pathways could be the future focus for stimulating endogenous cardiac regeneration in response to various pathological stressors. Meanwhile, patient-specific cardiomyocytes derived from autologous induced pluripotent stem cells (iPSCs) could become the major exogenous sources for replenishing the damaged myocardium. Human iPSC-derived cardiomyocytes (iPSC-CMs) are relatively immature and have the potential to increase the population of cells that advance to physiological hypertrophy in the presence of extracellular stimuli. In this review, we discuss how cardiac proliferation and maturation are regulated during embryonic development and postnatal growth, and explore how patient iPSC-CMs could serve as the future seed cells for cardiac cell replacement therapy.

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A calcineurin–Hoxb13 axis regulates growth mode of mammalian cardiomyocytes

Cited by 92 publications

References 40 publications

Dach1 extends artery networks and protects against cardiac injury

Dach1 extends artery networks and protects against cardiac injury

Regulation of cardiomyocyte fate plasticity: a key strategy for cardiac regeneration

Cardiomyocyte Proliferation and Maturation: Two Sides of the Same Coin for Heart Regeneration

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