Eomesodermin induces Mesp1 expression and cardiac differentiation from embryonic stem cells in the absence of Activin

Ameele, Jelle van den; Tiberi, Luca; Bondue, Antoine; Paulissen, Catherine; Herpoel, Adèle; Iacovino, Michelina; Kyba, Michael; Blanpain, Cédric; Vanderhaeghen, Pierre

doi:10.1038/embor.2012.23

Cited by 53 publications

(50 citation statements)

References 53 publications

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“…2B). EOMES has been suggested as a mesendoderm marker during hPSC differentiation [33] while MESP1 is generally considered as a cardiac mesoderm marker [34] that can be induced by EOMES [35, 36]. The observation that insulin does not inhibit EOMES expression but does block MESP1 expression further demonstrates that insulin inhibits cardiac mesoderm differentiation of hPSCs.…”

Section: Resultsmentioning

confidence: 99%

Insulin Inhibits Cardiac Mesoderm, Not Mesendoderm, Formation During Cardiac Differentiation of Human Pluripotent Stem Cells and Modulation of Canonical Wnt Signaling Can Rescue This Inhibition

et al. 2013

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The study of the regulatory signaling hierarchies of human heart development is limited by a lack of model systems that can reproduce the precise developmental events that occur during human embryogenesis. The advent of human pluripotent stem cell (hPSC) technology and robust cardiac differentiation methods affords a unique opportunity to monitor the full course of cardiac induction in vitro. Here we show that stage-specific activation of insulin signaling strongly inhibited cardiac differentiation during a monolayer-based differentiation protocol that used TGFβ superfamily ligands to generate cardiomyocytes. However, insulin did not repress cardiomyocyte differentiation in a defined protocol that employed small molecule regulators of canonical Wnt signaling. By examining the context of insulin inhibition of cardiomyocyte differentiation, we determined that the inhibitory effects by insulin required Wnt/β-catenin signaling and that the cardiomyocyte differentiation defect resulting from insulin exposure was rescued by inhibition of Wnt/β-catenin during the cardiac mesoderm (Nkx2.5+) stage. Thus, insulin and Wnt/β-catenin signaling pathways, as a network, coordinate to influence hPSC differentiation to cardiomyocytes, with the Wnt/β-catenin pathway dominant to the insulin pathway. Our study contributes to the understanding of the regulatory hierarchies of human cardiomyocyte differentiation and has implications for modeling human heart development.

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Section: Resultsmentioning

confidence: 99%

Insulin Inhibits Cardiac Mesoderm, Not Mesendoderm, Formation During Cardiac Differentiation of Human Pluripotent Stem Cells and Modulation of Canonical Wnt Signaling Can Rescue This Inhibition

et al. 2013

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“…Our work suggests that CARMEN functions upstream of and in the same regulatory pathway as EOMES and MESP1 in a miRNA-independent fashion, as a reprogramming factor necessary for cardiac commitment and differentiation of CPCs. Importantly, EOMES and MESP1 can specify all cell types of the cardiovascular lineage [43,44]. MESP1 is able to induce transdifferentiation of dermal fibroblasts into…”

Section: Mouse Es Cells With Deletions Of Both Mir-143 and Mir-145 Hamentioning

confidence: 99%

CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis

Ounzain

Micheletti

Arnan

et al. 2015

Journal of Molecular and Cellular Cardiology

241

215

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Long noncoding RNAs (lncRNAs) are emerging as important regulators of developmental pathways. However, their roles in human cardiac precursor cell (CPC) remain unexplored. To characterize the long noncoding transcriptome during human CPC cardiac differentiation, we profiled the lncRNA transcriptome in CPCs isolated from the human fetal heart and identified 570 lncRNAs that were modulated during cardiac differentiation. Many of these were associated with active cardiac enhancer and super enhancers (SE) with their expression being correlated with proximal cardiac genes. One of the most upregulated lncRNAs was a SE-associated lncRNA that was named CARMEN, (CAR)diac (M)esoderm (E)nhancer-associated (N)oncoding RNA. CARMEN exhibits RNA-dependent enhancing activity and is upstream of the cardiac mesoderm-specifying gene regulatory network. Interestingly, CARMEN interacts with SUZ12 and EZH2, two components of the polycomb repressive complex 2 (PRC2). We demonstrate that CARMEN knockdown inhibits cardiac specification and differentiation in cardiac precursor cells independently of MIR-143 and -145 expression, two microRNAs located proximal to the enhancer sequences. Importantly, CARMEN expression was activated during pathological remodeling in the mouse and human hearts, and was necessary for maintaining cardiac identity in differentiated cardiomyocytes. This study demonstrates therefore that CARMEN is a crucial regulator of cardiac cell differentiation and homeostasis.

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“…During the primitive streak stage of mouse embryonic development, the T-box transcription factor Eomesodermin ( Eomes ) activates the basic helix-loop-helix transcription factor Mesoderm Posterior 1 ( Mesp1 ). 11, 12 Mesp1 expression at the start of gastrulation represents the first known molecular step towards cardiogenesis. Mesp1 and family member Mesp2 are the earliest markers of cardiovascular specification in the developing embryo.…”

Section: Specification Of Cardiac Mesoderm and Formation Of The Cardimentioning

confidence: 99%

Molecular Regulation of Cardiomyocyte Differentiation

Paige¹,

Plonowska²,

Xu³

et al. 2015

Circulation Research

183

159

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The heart is the first organ to form during embryonic development. Given the complex nature of cardiac differentiation and morphogenesis, it is not surprising that some form of congenital heart disease is present in approximately one percent of newborns. The molecular determinants of heart development have received much attention over the past several decades. This has been driven in large part by an interest in understanding the etiology of congenital heart disease coupled with the potential of utilizing knowledge from developmental biology to generate functional cells and tissues that could be used for regenerative medicine purposes. In this review, we highlight the critical signaling pathways and transcription factor networks that regulate cardiomyocyte lineage specification in both in vivo and in vitro models. Special focus will be given to epigenetic regulators that drive the commitment of cardiomyogenic cells from nascent mesoderm and their differentiation into chamber-specific myocytes as well as regulation of myocardial trabeculation.

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Eomesodermin induces Mesp1 expression and cardiac differentiation from embryonic stem cells in the absence of Activin

Cited by 53 publications

References 53 publications

Insulin Inhibits Cardiac Mesoderm, Not Mesendoderm, Formation During Cardiac Differentiation of Human Pluripotent Stem Cells and Modulation of Canonical Wnt Signaling Can Rescue This Inhibition

Insulin Inhibits Cardiac Mesoderm, Not Mesendoderm, Formation During Cardiac Differentiation of Human Pluripotent Stem Cells and Modulation of Canonical Wnt Signaling Can Rescue This Inhibition

CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis

Molecular Regulation of Cardiomyocyte Differentiation

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