Article

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: 42.35). 04/2013; 497(7448). DOI: 10.1038/nature12054
Source: PubMed

ABSTRACT 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, Jul 30, 2015
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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 · 2.04 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
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    • "In addition, we did not observe any difference in AR and sham hearts of Meis1b transcripts (Figure 3G), and levels were decreasing with normal cardiac development (Figure 3H). This contradicts the suggested ability of increasing Meis1b levels to inhibit cardiomyocyte proliferation beyond P7 (Mahmoud et al., 2013). Therefore, our data do not support enhanced cardiomyocyte proliferation 1–7 days following AR as previously reported by Porrello et al. (2011). "
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    ABSTRACT: The mammalian heart has generally been considered nonregenerative, but recent progress suggests that neonatal mouse hearts have a genuine capacity to regenerate following apex resection (AR). However, in this study, we performed AR or sham surgery on 400 neonatal mice from inbred and outbred strains and found no evidence of complete regeneration. Ideally, new functional cardiomyocytes, endothelial cells, and vascular smooth muscle cells should be formed in the necrotic area of the damaged heart. Here, damaged hearts were 9.8% shorter and weighed 14% less than sham controls. In addition, the resection border contained a massive fibrotic scar mainly composed of nonmyocytes and collagen disposition. Furthermore, there was a substantial reduction in the number of proliferating cardiomyocytes in AR hearts. Our results thus question the usefulness of the AR model for identifying molecular mechanisms underlying regeneration of the adult heart after damage.
    Stem Cell Reports 04/2014; 2(4):406-13. DOI:10.1016/j.stemcr.2014.02.008
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