Endogenous IGF Signaling Directs Heterogeneous Mesoderm Differentiation in Human Embryonic Stem Cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE139625 | GEO | 2019/11/29
REPOSITORIES: GEO
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Project description:Endogenous IGF Signaling Directs Heterogeneous Mesoderm Differentiation in Human Embryonic Stem Cells
| PRJNA580510 | ENA
Project description:Cardiac mesoderm, a precursor for all cardiovascular lineages, is a promising cell source for basic research and clinical applications. BMP/Nodal/Wnt signaling induces cardiac mesoderm in embryonic stem cells (ESCs); however the molecular mechanism is unclear and the differentiation protocols are labor-intensive. Identification of a master regulator that induces cardiac mesoderm is needed. Here we found that Tbx6 directly reprogrammed mouse fibroblasts into cardiac mesoderm-like cells, which differentiated into cardiomyocytes and smooth muscle cells with addition of lineage-specific transcription factors. In mouse ESCs, BMP/Activin (Nodal) induced Tbx6 in cardiac mesoderm, while inhibition of Tbx6 blocked differentiation into cardiac mesoderm and cardiomyocytes. Conversely, transient expression of Tbx6 induced cardiac mesoderm in ESCs without exogenous factors, and generated all cardiovascular lineages. Mechanistically, Tbx6 directly upregulated Mesp1, inhibited Sox2, and activated BMP/Nodal/Wnt signaling to induce cardiac mesoderm. Thus, Tbx6 acts as a key regulator for cardiac mesoderm induction, and our findings provide new insights into the mechanism of cardiovascular differentiation.
2018-10-19 | GSE89820 | GEO
Project description:We compared the transcriptomes of EpiSCs maintained in the presence or absence of Wnt pathway inhibitor IWP2. We screened also our gene expression data for potential markers for genuine EpiSCs, maintained in the presence of Wnt inhibition and compared with ESC expression data. We compared the transcriptomes of EpiSCs maintained in the presence or absence of IWP2. The high level of Wnt-induced differentiation occurring in conventional EpiSC cultures may have interfered with the analysis of their characteristics. By applying Wnt inhibitors we are now able to establish the properties of genuine EpiSCs.
2014-12-24 | GSE62155 | GEO
Project description:Human embryonic stem cell (HES3) aggregates were differentiated into cardiomyocytes using biphasic WNT pathway modulation (CHIR99021 and IWP2) in 20mL scale using agitated Erlenmeyer Flask. On day 6 of differentiation, cells were treated with 1mM 1-EBIO or solvent control (DMSO) for 10 days.
2017-01-04 | E-MTAB-5192 | biostudies-arrayexpress
Project description:In hESCs, Wnt3/β-catenin activity is low and Activin/SMAD signaling ensures NANOG expression to sustain pluripotency. In response to exogenous Wnt3 effectors, Activin/SMADs switch to cooperate with β-catenin and induce mesendodermal differentiation genes. We show here that the HIPPO effector YAP binds to the WNT3 gene enhancer and prevents the gene from being induced by Activin in proliferating hESCs. In the absence of YAP, Activin signaling is sufficient to induce expression of the endogenous Wnt3 cytokine, which stabilizes β-catenin and selectively activates genes required for cardiac mesoderm (ME) formation. Interestingly, Activin-stimulated YAP-knockout hESCs strongly express β-catenin-dependent cardiac mesoderm markers (BAF60c and HAND1), but unlike WT hESCs, fail to express cardiac inhibitor genes (CDX2, MSX1). Accordingly, YAP-/- cells treated with Activin alone can differentiate efficiently to beating cardiomyocytes in culture, bypassing the need for sequential treatment with exogenous Wnt ligand and Wnt inhibitors. Similarly, Activin in combination with small-molecule YAP inhibitors generates beating cardiomyocytes from wild-type hESCs following a one- step protocol. Our findings highlight an unanticipated role of YAP as an upstream regulator of WNT3 to maintain hESC pluripotency in the presence of Activin, and uncover a direct route for the development of human embryonic cardiac mesoderm.
2018-01-08 | GSE99202 | GEO
Project description:Serine/threonine kinase 40 (Stk40) was previously identified as a direct target gene of pluripotency-associated transcription factor Oct4 and its overexpression could facilitate differentiation of mouse embryonic stem cells (mESCs) towards the extraembryonic endoderm. Stk40-/- mice are lethal at the perinatal stage, displaying multiple organ failures. However, the molecular mechanisms underlying the physiological functions of Stk40 remain elusive. Here, we report that Stk40 ablation compromises the mesoderm differentiation from mESCs in vitro and in embryos. Mechanistically, Stk40 interacts with both mammalian constitutive photomorphogenic protein 1 (Cop1) and c-Jun, promoting degradation of c-Jun. Consequently, Stk40 knockout leads to c-Jun protein accumulation, which, in turn, might suppress the Wnt signaling activity and impair the mesoderm differentiation process. Overall, this study reveals that Stk40, together with Cop1, represent a novel axis for modulating c-Jun protein levels within an appropriate range during mesoderm differentiation from mESCs. Our finding provides new insight into the molecular mechanism regulating c-Jun protein stability and may have potential for managing related cellular disorders.
2019-05-14 | PXD012579 | Pride
Project description:Cardiac lineage specification in the mouse is controlled by TGFβ and WNT signaling. From fly to fish, BMP has been identified as an indispensable heart inducer. A detailed analysis of the role of Bmp4 and its effectors Smad1/5, however, was still missing. We show that Bmp4 induces cardiac mesoderm formation in murine embryonic stem cells in vitro. Bmp4 first activates Wnt3 and upregulates Nodal. pSmad1/5 and the WNT effector Tcf3 form a complex, and together with pSmad2/3 activate mesoderm enhancers and Eomes. They then cooperate with Eomes to consolidate the expression of many mesoderm factors, including T. Eomes and T form a positive feedback loop and open additional enhancers regulating early mesoderm genes, including the transcription factor Mesp1 establishing the cardiac mesoderm lineage. In parallel, the neural fate is suppressed. Our data confirm the pivotal role of Bmp4 in cardiac mesoderm formation in the mouse. We describe in detail the consecutive and cooperative actions of three signaling pathways, BMP, WNT and Nodal, and their effector transcription factors, during cardiac mesoderm specification.
2023-05-03 | GSE168580 | GEO
Project description:We compared differential gene expression between WT and BRM KO in mesoderm, cardiac precursors and cardiomyocytes
2021-10-27 | GSE116292 | GEO
Project description:The trunk axial skeleton develops from paraxial mesoderm cells. Our recent study demonstrated that conditional knockout of the stem cell factor Sall4 in mice by TCre caused tail truncation and a disorganized axial skeleton posterior to the lumbar level. Based on this phenotype, we hypothesized that, in addition to the previously reported role of Sall4 in neuromesodermal progenitors, Sall4 is involved in the development of the paraxial mesoderm tissue. ATAC-seq in TCre; Sall4 mutant posterior trunk mesoderm shows that Sall4 knockout reduces chromatin accessibility. We found that Sall4- dependent open chromatin status drives activation and repression of WNT signaling activators and repressors, respectively, to promote WNT signaling. Moreover, footprinting analysis of ATAC-seq data suggests that Sall4-dependent chromatin accessibility facilitates CTCF binding, which contributes to the repression of neural genes within the mesoderm. This study unveils multiple mechanisms by which Sall4 regulates paraxial mesoderm development by directing activation of mesodermal genes and repression of neural genes.
2024-02-13 | GSE217671 | GEO
Project description:Among the three embryonic germ layers, mesoderm plays a central role in the establishment of the vertebrate body plan. Mesoderm is specified by secreted signaling proteins from the FGF, Nodal, BMP and Wnt families. No new classes of extracellular mesoderm-inducing factors have been identified in more than two decades. Here we show that the Xenopus pinhead (pnhd) gene encodes a novel secreted protein that activates specific mesodermal markers in presumptive ectoderm. We demonstrate that Pnhd is required for the specification of a subset of embryonic mesoderm in vivo. RNA sequencing revealed that many transcriptional targets of Pnhd are shared with those of the FGF pathway. Pnhd signaling involves active FGF but not Wnt receptors and is accompanied by Erk1 phosphorylation. We propose that Pnhd operates in the marginal zone to specify mesodermal progenitors via an FGF receptor-dependent mechanism.
2020-05-15 | GSE143795 | GEO