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Breaking the first lineage barrier: Direct induction of trophoblast stem cells from murine fibroblasts

ABSTRACT: Trophoblast stem cells represent the stem cell population of the extra-embryonic lineage and arise as a result of the first cell fate decision. From blastocyst stage onwards, a distinct epigenetic lineage barrier strictly separates mouse embryonic and extra-embryonic lineages. Recently, it has been shown that this epigenetic barrier cannot be fully overcome as the expression of TS-determining factors in embryonic stem cells lead to incomplete transdifferentiation. Here, we demonstrate that transient expression of Tfap2c, Gata3, Eomes and Ets2 in fibroblasts suffices to generate cells which are almost identical to trophoblast stem cells based on morphology, expression and methylation pattern. Further, these induced trophoblast stem cells display transgene independent self-renewal, differentiate along the extra-embryonic lineage and chimerize the placenta upon blastocyst injection. Our findings provide insights into the transcription factor networks governing trophoblast stem cell identity and offer a new tool for studying the hierarchy of those factors.

ORGANISM(S): Mus musculus

PROVIDER: GSE64145 | GEO | 2015/10/01

SECONDARY ACCESSION(S): PRJNA270252

REPOSITORIES: GEO

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Breaking the lineage barrier: Direct induction of trophoblast stem cells from murine fibroblasts

Project description:Trophoblast stem cells represent the stem cell population of the extraembryonic lineage and arise as result of the first cell fate decision. From the blastocyst stage onwards, the extraembryonic lineage is strictly separated from the embryonic lineage by a distinct epigenetic lineage barrier. Recently, it has been shown, that this epigenetic barrier cannot be fully overcome as the expression of TS-determining factors in embryonic stem cells lead to incomplete trans-differentiation. Here we demonstrate that transient expression of Tfap2c, Gata3, Eomes and Ets2 in fibroblasts suffices to generate cells, which are almost equivalent to trophoblast stem cells based on morphology, expression and methylation patterns. Further, these induced trophoblast stem cells display self-renewal without exogenous factor expression, differentiate along the extraembryonic lineage and chimerize the placenta upon blastocyst injection. Our findings provide insights into transcription factor networks governing TSC identity and offer a new tool for studying the hierarchy of those factors.

2015-10-01 | GSE64339 | GEO

Gata3 acts alongside Cdx2 to promote trophoblast gene expression downstream of Tead4 during mouse development

Project description:The first lineage decisions during mouse development lead to establishment of embryonic and extraembryonic tissues. The transcription factor Cdx2 plays a central role by repressing pluripotency genes, such as Oct4 and promoting trophoblast fate at the blastocyst stage. Here we show that the transcription factor Gata3 is coexpressed with Cdx2 in the blastocyst and that overexpression of Gata3 in embryonic stem cells is sufficient to induce expression of trophoblast genes. Gata3 expression in the blastocyst does not depend on Cdx2, nor do Gata3 overexpressing cell lines require Cdx2 for expression of a subset of trophoblast genes. In the embryo, expression of Gata3, like Cdx2, depends on Tead4, and expression of both factors becomes restricted to nascent trophoblast by an Oct4-independent mechanism. These observations place Tead4 at the top of a trophoblast hierarchy, with Gata3 and Cdx2 acting downstream to induce expression of common and independent targets in this lineage. This SuperSeries is composed of the following subset Series: GSE12985: Differentiation time course of trophoblast stem cells GSE12986: Expression of Cdx2 or Gata3 in R1 mouse embryonic stem cells

2010-02-21 | E-GEOD-12999 | biostudies-arrayexpress

Naïve human embryonic stem cells can give rise to cells with trophoblast-like transcriptome and methylome [RNA-Seq]

Project description:Human embryonic stem cells (hESCs) readily differentiate to somatic or germ lineages but have impaired ability to form extra-embryonic lineages such as placenta or yolk sac. Here we demonstrate that hESCs cultured in naïve media conditions can be converted into cells that exhibit the cellular and molecular phenotypes of human trophoblast stem cells (hTSCs) derived from human placenta or blastocyst. The resulting “transdifferentiated” hTSCs show reactivation of core placental genes, acquisition of a placenta-like methylome, and the ability to differentiate to extravillous trophoblasts and syncytiotrophoblasts. Modest differences are observed between transdifferentiated and placental hTSCs, most notably in the expression of certain imprinted loci. These results indicate that naïve hESCs can differentiate to extra-embryonic lineage, and demonstrate a new way of modeling human trophoblast specification and placental methylome establishment.

2020-06-16 | GSE152101 | GEO

Naïve human embryonic stem cells can give rise to cells with trophoblast-like transcriptome and methylome [Bisulfite-Seq]

2020-06-16 | GSE150168 | GEO

Integrated Multi-Omics Reveal Polycomb Repressive Complex 2 Restricts Human Trophoblast Induction

Project description:Human naive pluripotent stem cells have unrestricted lineage potential. Underpinning this property, naive cells are thought to lack chromatin-based lineage barriers. However, this assumption has not been tested. Here, we define the chromatin-associated proteome, histone post-translational modifications and transcriptome of human naive and primed pluripotent stem cells. Our integrated analysis reveals differences in the relative abundance and activities of distinct chromatin modules. We identify a strong enrichment of Polycomb Repressive Complex 2 (PRC2)-associated H3K27me3 in naive pluripotent stem cell chromatin, and H3K27me3 enrichment at promoters of lineage-determining genes, including trophoblast regulators. PRC2 activity acts as a chromatin barrier restricting the differentiation of naive cells towards the trophoblast lineage, while inhibition of PRC2 promotes trophoblast fate induction and cavity formation in human blastoids. Together, our results establish that human naive pluripotent stem cells are not epigenetically unrestricted, but instead possess chromatin mechanisms that oppose the induction of alternative cell fates.

2022-05-09 | PXD032792 | Pride

Gata3 acts alongside Cdx2 to promote trophoblast gene expression downstream of Tead4 during mouse development

2010-02-01 | GSE12999 | GEO

Human embryo and trophoblast proteome

Project description:Comprehensive quantitative proteomic study of human pre-implantation embryo stages reveal dynamic proteome landscape from M2, 8-cell and blastocyst stage, and during trophoblast stem cell (TS) differentiation. Identified key factors in early human embryos and lineage-specific trophoblast proteome profiles, correlated with transcriptomic analyses. This direct proteomic analysis provides a comprehensive analysis of the dynamic protein expression in human embryos during pre-implantation development and a powerful resource to enable further mechanistic studies on human trophoblast development and function.

2023-07-05 | MSV000092349 | MassIVE

Polycomb Repressive Complex 2 Restricts Human Naive Pluripotent Stem Cell to Trophoblast Fate Induction

Project description:Human naive pluripotent stem cells have unrestricted lineage potential. Underpinning this property, naive cells are thought to lack chromatin-based lineage barriers. However, this assumption has not been tested. Here, we apply multi-omics to comprehensively define the chromatin-associated proteome, histone post-translational modifications and transcriptome of human naive and primed pluripotent stem cells. Integrating the chromatin-bound proteome and histone modification data sets reveals differences in the relative abundance and activities of distinct chromatin modules, identifying a strong enrichment of Polycomb Repressive Complex 2 (PRC2)-associated H3K27me3 in naive pluripotent stem cell chromatin. Single-cell approaches and human blastoid models reveal that PRC2 activity acts as a chromatin barrier restricting the differentiation of naive cells towards the trophoblast lineage, and inhibiting PRC2 promotes trophoblast fate induction and cavity formation. Our results establish that human naive pluripotent stem cells are not epigenetically unrestricted, but instead possess chromatin mechanisms that oppose the induction of alternative cell fates.

2022-05-06 | PXD028111 | Pride

Cell-to-cell gene expression variability followed by reinforcement progressively segregates lineages in the early mouse embryo

Project description:Mammalian embryonic development begins with the specification and segregation of the two extra-embryonic lineages, trophectoderm and primitive endoderm, from the pluripotent embryonic lineage, the epiblast. To establish a map of epiblast (EPI) versus primitive endoderm (PrE) lineage segregation which occurs within the inner cell mass (ICM), we comprehensively characterised the gene expression profiles of individual inner cells during blastocyst development. Lineage represents the two embryonic cell lineages: the epiblast (EPI), and the primitive endoderm (PE), which are segregated within the inner cell mass(ICM) during blastocyst development.

2013-11-26 | E-MTAB-1681 | biostudies-arrayexpress

Integrated Multi-Omics Reveal Polycomb Repressive Complex 2 Restricts Human Trophoblast Induction

Project description:Human naive pluripotent stem cells have unrestricted lineage potential. Underpinning this property, naive cells are thought to lack chromatin-based lineage barriers. However, this assumption has not been tested. Here, we apply multi-omics to comprehensively define the chromatin-associated proteome, histone post-translational modifications and transcriptome of human naive and primed pluripotent stem cells. Integrating the chromatin-bound proteome and histone modification data sets reveals differences in the relative abundance and activities of distinct chromatin modules, identifying a strong enrichment of Polycomb Repressive Complex 2 (PRC2)-associated H3K27me3 in naive pluripotent stem cell chromatin. Single-cell approaches and human blastoid models reveal that PRC2 activity acts as a chromatin barrier restricting the differentiation of naive cells towards the trophoblast lineage, and inhibiting PRC2 promotes trophoblast fate induction and cavity formation. Our results establish that human naive pluripotent stem cells are not epigenetically unrestricted, but instead possess chromatin mechanisms that oppose the induction of alternative cell fates. Data originating from the LC-MS/MS analysis of the histone PTMs can be consulted via this project.

2022-05-06 | PXD028162 | Pride

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