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A calcineurin-Hoxb13 axis regulates growth mode of mammalian cardiomyocytes.

ABSTRACT: A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes^1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest³. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of cardiomyocyte proliferation and reactivate the cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1-Hoxb13 double-knockout hearts display widespread cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of cardiomyocytes.

SUBMITTER: Nguyen NUN

PROVIDER: S-EPMC7670845 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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A calcineurin-Hoxb13 axis regulates growth mode of mammalian cardiomyocytes.

Nguyen Ngoc Uyen Nhi NUN Canseco Diana C DC Xiao Feng F Nakada Yuji Y Li Shujuan S Lam Nicholas T NT Muralidhar Shalini A SA Savla Jainy J JJ Hill Joseph A JA Le Victor V Zidan Kareem A KA El-Feky Hamed W HW Wang Zhaoning Z Ahmed Mahmoud Salama MS Hubbi Maimon E ME Menendez-Montes Ivan I Moon Jesung J Ali Shah R SR Le Victoria V Villalobos Elisa E Mohamed Magid S MS Elhelaly Waleed M WM Thet Suwannee S Anene-Nzelu Chukwuemeka George CG Tan Wilson Lek Wen WLW Foo Roger S RS Meng Xun X Kanchwala Mohammed M Xing Chao C Roy Jagoree J Cyert Martha S MS Rothermel Beverly A BA Sadek Hesham A HA

Nature 20200422 7811

A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes<sup>1,2</sup> and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest< ...[more]

PMID: 32499640

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Project description:BackgroundIt has long been thought that mammalian cardiomyocytes are terminally-differentiated and unable to proliferate. However, myocytes in more primitive animals such as zebrafish are able to dedifferentiate and proliferate to regenerate amputated cardiac muscle.Methodology/principal findingsHere we test the hypothesis that mature mammalian cardiomyocytes retain substantial cellular plasticity, including the ability to dedifferentiate, proliferate, and acquire progenitor cell phenotypes. Two complementary methods were used: 1) cardiomyocyte purification from rat hearts, and 2) genetic fate mapping in cardiac explants from bi-transgenic mice. Cardiomyocytes isolated from rodent hearts were purified by multiple centrifugation and Percoll gradient separation steps, and the purity verified by immunostaining and RT-PCR. Within days in culture, purified cardiomyocytes lost their characteristic electrophysiological properties and striations, flattened and began to divide, as confirmed by proliferation markers and BrdU incorporation. Many dedifferentiated cardiomyocytes went on to express the stem cell antigen c-kit, and the early cardiac transcription factors GATA4 and Nkx2.5. Underlying these changes, inhibitory cell cycle molecules were suppressed in myocyte-derived cells (MDCs), while microRNAs known to orchestrate proliferation and pluripotency increased dramatically. Some, but not all, MDCs self-organized into spheres and re-differentiated into myocytes and endothelial cells in vitro. Cell fate tracking of cardiomyocytes from 4-OH-Tamoxifen-treated double-transgenic MerCreMer/ZEG mouse hearts revealed that green fluorescent protein (GFP) continues to be expressed in dedifferentiated cardiomyocytes, two-thirds of which were also c-kit(+).Conclusions/significanceContradicting the prevailing view that they are terminally-differentiated, postnatal mammalian cardiomyocytes are instead capable of substantial plasticity. Dedifferentiation of myocytes facilitates proliferation and confers a degree of stemness, including the expression of c-kit and the capacity for multipotency.

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A calcineurin-Hoxb13 axis regulates growth mode of mammalian cardiomyocytes.

Publications

A calcineurin-Hoxb13 axis regulates growth mode of mammalian cardiomyocytes.

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