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Sustained intrinsic WNT and BMP4 activation impairs hESC differentiation to definitive endoderm and drives the cells towards extra-embryonic mesoderm

ABSTRACT: Sustained intrinsic WNT and BMP4 activation impairs hESC differentiation to definitive endoderm and drives the cells towards extra-embryonic mesoderm

PROVIDER: PRJNA555431 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9705430.fastq.gz	Fastqsanger.gz
	SRR9705431.fastq.gz	Fastqsanger.gz
	SRR9705432.fastq.gz	Fastqsanger.gz
	SRR9701023.fastq.gz	Fastqsanger.gz
	SRR9705433.fastq.gz	Fastqsanger.gz

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Sustained intrinsic WNT and BMP4 activation impairs hESC differentiation to definitive endoderm and drives the cells towards extra-embryonic mesoderm.

Project description:We identified a human embryonic stem cell subline that fails to respond to the differentiation cues needed to obtain endoderm derivatives, differentiating instead into extra-embryonic mesoderm. RNA-sequencing analysis showed that the subline has hyperactivation of the WNT and BMP4 signalling. Modulation of these pathways with small molecules confirmed them as the cause of the differentiation impairment. While activation of WNT and BMP4 in control cells resulted in a loss of endoderm differentiation and induction of extra-embryonic mesoderm markers, inhibition of these pathways in the subline restored its ability to differentiate. Karyotyping and exome sequencing analysis did not identify any changes in the genome that could account for the pathway deregulation. These findings add to the increasing evidence that different responses of stem cell lines to differentiation protocols are based on genetic and epigenetic factors, inherent to the line or acquired during cell culture.

| S-EPMC8050086 | biostudies-literature

Sustained intrinsic WNT and BMP4 activation impairs hESC differentiation to definitive endoderm and drives the cells towards extra-embryonic mesoderm

Project description:This dataset includes the RNA sequencing of five replicates of the undifferentiated hESC subline VUB03_S2, which shows impaired mesendoderm induction, and 14 WT samples from GSE116372.

2021-04-06 | GSE134454 | GEO

Synergism between Activin A and BMP4 in directing the formation of definitive endoderm in human embryonic stem cells

Project description:Human embryonic stem cells (HESCs) herald tremendous promise for the production of clinically useful cell types for the treatment of injury and disease. Numerous reports demonstrate their differentiation into definitive endoderm (DE) cells, the germ layer from which pancreatic β cells and hepatocytes arise, solely from exposure to a high dose of recombinant Activin/Nodal. Here, we show that combining a second related ligand, BMP4, in combination with Activin A yields 15 to 20% more DE as compared to Activin A alone. The addition of recombinant BMP4 accelerates the downregulation of pluripotency factors, particularly SOX2, and results in upregulation of endogenous BMP2 and BMP4, which in turn leads to elevated levels of phospho-SMAD1/5/8 over the next three days of differentiation. Combined Activin A and BMP4 treatment also leads to an increase in the expression of DE genes CXCR4, SOX17 and FOXA2 when compared to Activin A addition alone. Comparative microarray studies between DE cells harvested on day 3 of differentiation further reveal a novel set of genes upregulated in response to initial BMP4 exposure. Several of these, including APLNR, LRIG3, MCC and LZTS1, are expressed either in the mouse primitive streak, the site of DE formation, or in nascent DE itself. Thus, this synergism between Activin A and BMP4 during the in vitro differentiation of HESC into DE suggests a complex interplay between BMP and Activin/Nodal signaling during the in vivo allocation and expansion of the endoderm lineage. 3 biological replicates of 3-day ActivinA treated HES3 human stem cell culture were compared to 3-day ActivinA+Bmp4 treated HES3 human stem cell culture and observed for differential genes expression

2011-11-10 | E-GEOD-30630 | biostudies-arrayexpress

Synergism between Activin A and BMP4 in directing the formation of definitive endoderm in human embryonic stem cells

2011-11-10 | GSE30630 | GEO

BMP4 triggers regulatory circuits specifying the cardiac mesoderm lineage

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

Transcription profiling of human embryonic stem cells treated with BMP4 in chemically-defined medium, with and without inhibitors of Activin and FGF signalling to investigate the induction of extra-embryonic tissue differentiation by BMP signalling

Project description:Gene expression microarray analysis of hESCs treated with BMP4 in chemically-defined medium, with and without inhibitors of Activin and FGF signalling (which maintain pluripotency), to investigate the induction of extra-embryonic tissue (trophectoderm) differentiation by BMP signalling.

2009-07-31 | E-MEXP-1192 | biostudies-arrayexpress

Circulating endoglin induces hypertension via the upregulated expression of BMP4

Project description:Endoglin is a membrane glycoprotein primarily expressed by the vascular endothelium and involved in cardiovascular diseases. Upon the proteolytic processing of the membrane-bound protein, a circulating form of endoglin (soluble endoglin, sEng) can be released, and high levels of sEng have been observed in several endothelial-related pathological conditions, where it appears to contribute to endothelial dysfunction. Preeclampsia is a multisystem disorder of high prevalence in pregnant women characterized by the onset of high blood pressure and often associated with increased levels of sEng. Although a pathogenic role for sEng involving hypertension has been reported in several animal models of preeclampsia, the exact molecular mechanisms implicated remain to be identified. To search for sEng-induced mediators, we have analyzed the protein secretome of human endothelial cells in the presence of sEng. We find that sEng induces the expression of BMP4 in endothelial cells, as evidenced by their proteomic signature, gene transcript levels and BMP4 promoter activity. A mouse model of preeclampsia with high sEng plasma levels (sEng+) showed increased levels of BMP4 transcripts in lungs and increased circulating BMP4, compared to those of control animals. In addition, after crossing female wild type with male sEng+ mice, hypertension appears 18 days after mating, precisely coinciding with the appearance of high plasma levels of BMP4. Also, serum levels of sEng and BMP4 are positively correlated in pregnant women with and without preeclampsia. Interestingly, sEng-induced arterial pressure elevation in sEng+ mice was abolished in the presence of the BMP4 inhibitor noggin, suggesting that BMP4 is a downstream mediator of sEng. These results provide a better understanding on the role of sEng in the pathobiology of preeclampsia and other cardiovascular diseases, where sEng levels are increased.

2020-04-23 | PXD016228 | Pride

Transcriptome profiling of hESC-derived endoderm progenitors by single-cell RNA-seq

Project description:In this study, we characterised transcriptomes of hESC-derived transient anterior definitive endoderm (ADE) and expanding ventral foregut (VFG) culture by single-cell sequencing. We also examined the effect of BMP4 withdrawal and FGF2 stimulation in the VFG culture.

2022-11-15 | GSE188362 | GEO

BMP4 triggers regulatory circuits specifying the cardiac mesoderm lineage

Project description:BMP4 triggers regulatory circuits specifying the cardiac mesoderm lineage

| PRJNA708331 | ENA

Compare transcriptomes of BMP4 and BMP4 plus Palo treatment in 2H11 cells

Project description:In order to observe palovarotene modulates BMP4-induced transcriptome,2H11 cells treated with BMP4 or BMP4 plus palovarotene for 48 hours were subjected to RNAseq analyses

2021-03-04 | GSE168157 | GEO

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