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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150168 | GEO | 2020/06/16

REPOSITORIES: GEO

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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

Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids

Project description:Zika virus (ZIKV) infection during pregnancy results in an increased risk of spontaneous abortion and vertical transmission across placenta results in severe congenital defects in newborns. While the infectivity and pathological effects of ZIKV on the placental trophoblast progenitor cells in early human embryos remains largely unknown. Here, using the human trophoblast stem cells (hTSCs) isolated from human blastocyst, we showed that hTSCs were permissive to ZIKV infection, while resistance to ZIKV increased with differentiation. Combined CRISPR/Cas9-mediated gene knockout and RNA-seq assays, we demonstrated that the intrinsic expression of AXL and TIM-1, as well as the absence of potent interferon (IFN)-stimulated genes (ISGs), contributed to the high sensitivity of hTSCs to ZIKV. Furthermore, using our newly developed hTSC-derived 3 dimensional (3D) placental trophoblast organoid model, we demonstrated that ZIKV infection completely disrupted the structure of mature hTSC-organoids and inhibited syncytialization. Overall, our results clearly demonstrated that hTSCs represented the major target cells of ZIKV, and a possible reduced syncytialization may result from ZIKV infection of early developing placenta. These findings deepened our understanding of the characteristics and consequences of ZIKV infection of trophoblast stem cells in early human embryo.

2023-08-03 | GSE229702 | GEO

CRISPR screening in human trophoblast stem cells reveals both shared and distinct aspects of human and mouse placental development [ChIP-seq]

Project description:The placenta serves as the interface between the mother and fetus, facilitating the exchange of gases and nutrients between their separate blood circulation systems. Trophoblasts in the placenta play a central role in this process. Our current understanding of mammalian trophoblast development relies largely on mouse models. However, given the diversification of mammalian placentas, findings from the mouse placenta cannot be readily extrapolated to other mammalian species, including humans. To fill this knowledge gap, we performed CRISPR knockout (KO) screening in human trophoblast stem cells (hTSCs). We targeted genes essential for mouse placental development and identified more than 100 genes as critical regulators in both human hTSCs and mouse placentas. Among them, we further characterized in detail two transcription factors, DLX3 and GCM1, and revealed their essential roles in hTSC differentiation. Moreover, a gene function-based comparison between human and mouse trophoblast subtypes suggests that their relationship may differ significantly from previous assumptions based on tissue localization or cellular function. Notably, our data reveal that hTSCs may not be analogous to mouse TSCs or the extraembryonic ectoderm (ExE) in which in vivo TSCs reside. Instead, hTSCs may be analogous to progenitor cells in the mouse ectoplacental cone and chorion. This finding is consistent with the absence of ExE-like structures during human placental development. Our data not only deepen our understanding of human trophoblast development but also facilitate cross-species comparison of mammalian placentas.

2023-11-09 | GSE244252 | GEO

CRISPR screening in human trophoblast stem cells reveals both shared and distinct aspects of human and mouse placental development [HiChIP]

2023-11-09 | GSE244253 | GEO

CRISPR screening in human trophoblast stem cells reveals both shared and distinct aspects of human and mouse placental development [RNA-seq]

2023-11-09 | GSE244254 | GEO

Induction of trophoblast stem cells from human pluripotent stem cells [RNA-seq]

Project description:In human, the functional placenta requires the proper differentiation of trophoblastic subtypes from the trophoblast stem cells (hTSCs). Although successful derivation of hTSCs from the early placentas and blastocysts, these hTSCs face ethical concerns and limited models for trophoblast-related disorders at later stage, such as preeclampsia. Here, we show that both hESCs and hiPSCs are able to be induced to the long-term and proliferative hTSCs under defined culture medium. These induced trophoblast stem cells (iTSCs) are comparable to the hTSC cell line derived from blastocyst in morphology, growth properties, specific genes expression, capacity of differentiating toward extravillous cytotrophoblast and syncytiotrophoblast, and patterns of transcriptome profile, chromatin accessibility and histone modification that are conducive to placenta development and maintenance of hTSCs. Notably, iTSCs meet four criteria defining "trophoblastic" including: expression of specific transcript factors, hypomethylation of ELF5 promoter, lack of expression of HLA-class I molecules and expression of the chromosome 19-encoded miRNA. Moreover, we reveal that addition of BMP4 or absence of H3K27 methyltransferases EZH1/2 could enhance the iTSCs generation. Our results suggest that human TS cells could be derived from human pluripotent stem cells, which expands the source of human TS cells avoiding ethic issues and provides a useful tool for researching placenta development and function, and modeling placenta-originated disorders.

2021-08-16 | GSE135695 | GEO

Induction of trophoblast stem cells from human pluripotent stem cells [ChIP-seq]

2021-08-16 | GSE135694 | GEO

Induction of trophoblast stem cells from human pluripotent stem cells [ATAC-seq]

2021-08-16 | GSE135693 | GEO

Methylation profiling of human trophoblast organoids providing a model for maternal-fetal interactions in early pregnancy and placenta tissue for comparison

Project description:Generation of long-term, genetically-stable organoid cultures of extra-embryonic fetal trophoblast cells from human early placentas. Methylation profiling of the human trophoblast organoids and early placenta tissue.

2018-11-28 | E-MTAB-7204 | biostudies-arrayexpress

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

Project description: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.

2015-10-01 | GSE64145 | GEO

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