Meis1 regulates postnatal cardiomyocyte cell cycle arrest

1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2].
Nature (Impact Factor: 41.46). 04/2013; 497(7448). DOI: 10.1038/nature12054
Source: PubMed


The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation. However, this regenerative capacity is lost by postnatal day 7 and the mechanisms of cardiomyocyte cell cycle arrest remain unclear. The homeodomain transcription factor Meis1 is required for normal cardiac development but its role in cardiomyocytes is unknown. Here we identify Meis1 as a critical regulator of the cardiomyocyte cell cycle. Meis1 deletion in mouse cardiomyocytes was sufficient for extension of the postnatal proliferative window of cardiomyocytes, and for re-activation of cardiomyocyte mitosis in the adult heart with no deleterious effect on cardiac function. In contrast, overexpression of Meis1 in cardiomyocytes decreased neonatal myocyte proliferation and inhibited neonatal heart regeneration. Finally, we show that Meis1 is required for transcriptional activation of the synergistic CDK inhibitors p15, p16 and p21. These results identify Meis1 as a critical transcriptional regulator of cardiomyocyte proliferation and a potential therapeutic target for heart regeneration.

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Available from: Ahmed I Mahmoud, Oct 03, 2015
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    • "Quantification of the pH3 positive cardiomyocytes showed a significant decrease in the number of proliferating cardiomyocytes in resected plus vagotomized mice compared to resection alone (Figure S2B, n = 5, p < 0.05). Similar to regeneration following apical resection, neonatal mice have the capacity to regenerate their hearts following myocardial infarction (MI), a major cause of heart failure in humans (Mahmoud et al., 2014; Porrello et al., 2013). We performed both MI + vagotomy on 1-day-old mice (Figure 4A). "
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    ABSTRACT: Some organisms, such as adult zebrafish and newborn mice, have the capacity to regenerate heart tissue following injury. Unraveling the mechanisms of heart regeneration is fundamental to understanding why regeneration fails in adult humans. Numerous studies have revealed that nerves are crucial for organ regeneration, thus we aimed to determine whether nerves guide heart regeneration. Here, we show using transgenic zebrafish that inhibition of cardiac innervation leads to reduction of myocyte proliferation following injury. Specifically, pharmacological inhibition of cholinergic nerve function reduces cardiomyocyte proliferation in the injured hearts of both zebrafish and neonatal mice. Direct mechanical denervation impairs heart regeneration in neonatal mice, which was rescued by the administration of neuregulin 1 (NRG1) and nerve growth factor (NGF) recombinant proteins. Transcriptional analysis of mechanically denervated hearts revealed a blunted inflammatory and immune response following injury. These findings demonstrate that nerve function is required for both zebrafish and mouse heart regeneration. Copyright © 2015 Elsevier Inc. All rights reserved.
    Developmental Cell 08/2015; 34(4). DOI:10.1016/j.devcel.2015.06.017 · 9.71 Impact Factor
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    • "Genome-wide association studies have also found an association of Meis1 with Restless Legs Syndrome (Spieler et al., 2014; Winkelmann et al., 2007) and cardiac conduction defects (Butler et al., 2012; Pfeufer et al., 2010; Smith et al., 2011). Recently, Meis1 was found to be implicated in cardiomyocyte differentiation (Wamstad et al., 2012) and in the control of proliferation of post-natal myocardium (Mahmoud et al., 2013). Several mouse models with targeted mutations in the Meis1 locus have been described. "
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    ABSTRACT: Meis1 is a highly conserved transcription factor that is activated in a regionally restricted manner from early stages of development. Meis1 belongs to the three amino acid loop extension (TALE) homeodomain family. Together with Pbx1, Meis1 plays a major role as a Hox cofactor and therefore plays an essential role in the development of several embryonic organs and systems, including limbs, heart, blood and vasculature. In addition Meis1 is required for the development of Hox-free embryonic regions and interacts with non-Hox homeodomain and non-homeodomain transcription factors. During postnatal life Meis1 is involved in adult cardiomyocyte homeostasis and has been associated with predisposition to human neural and cardiac pathologies. Given the relevance of this transcription factor, we have developed two new Meis1 gene knockin models; a direct ECFP knockin insertion that allows the direct identification of Meis1-expressing cells in living tissues, and a CreERT2 insertion that allows the inducible genetic tracing of Meis1-expressing cells in a time-controlled manner. Importantly, these two alleles represent the first Meis1 mutations in which Meis1 protein production is completely eliminated. These newly targeted Meis1 alleles will be valuable tools to further our understanding of the role of this critical transcription factor during development and disease. © 2014 Wiley Periodicals, Inc.
    genesis 12/2014; 52(12). DOI:10.1002/dvg.22833 · 2.02 Impact Factor
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    • "The TnT subunit has been used extensively in attempt to identify the cardiac lineage (Chan et al., 2013b; Hazeltine et al., 2013; Kawamura et al., 2013; Park et al., 2014; Rebuzzini et al., 2013). However, cTnT is also expressed in noncardiac cells such as smooth muscle cells (Porrello et al., 2011, 2013; Lu et al., 2013; Lundy et al., 2013; Mahmoud et al., 2013; Xin et al., 2013), limiting its use as a cardiac lineage marker. Many other structural, regulatory, morphological, and metabolic markers have been used for cardiac lineage and maturation assignment; however, these are subject to reversion to the fetal program in stress and disease. "
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    ABSTRACT: There is no consensus in the stem cell field as to what constitutes the mature cardiac myocyte. Thus, helping formalize a molecular signature for cardiac myocyte maturation would advance the field. In the mammalian heart, inactivation of the "fetal" TNNI gene, TNNI1 (ssTnI), together in temporal concert with its stoichiometric replacement by the adult TNNI gene product, TNNI3 (cTnI), represents a quantifiable ratiometric maturation signature. We examined the TNNI isoform transition in human induced pluripotent stem cell (iPSC) cardiac myocytes (hiPSC-CMs) and found the fetal TNNI signature, even during long-term culture. Rodent stem cell-derived and primary myocytes, however, transitioned to the adult TnI profile. Acute genetic engineering of hiPSC-CMs enabled a rapid conversion toward the mature TnI profile. While there is no single marker to denote the mature cardiac myocyte, we propose that tracking the cTnI:ssTnI protein isoform ratio provides a valuable maturation signature to quantify myocyte maturation status across laboratories.
    Stem Cell Reports 10/2014; 3(4). DOI:10.1016/j.stemcr.2014.07.012 · 5.37 Impact Factor
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