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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE135695 | GEO | 2021/08/16

REPOSITORIES: GEO

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Induction of trophoblast stem cells from human pluripotent stem cells [ChIP-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 | GSE135694 | GEO

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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.

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A genome-wide CRISPR-Cas9 knockout screen identifies essential and growth-restricting genes in human trophoblast stem cells

Project description:The recent derivation of bona fide human trophoblast stem cells (hTSCs) significantly improved our ability to study human placental biology and pathologies, but few studies have investigated the molecular regulators of hTSC identity. Therefore, we utilized a genome-wide CRISPR-Cas9 knockout screen to comprehensively define genes essential for or restricting the fitness of hTSCs. The resulting essential and growth-restricting genes include both well-established and potentially novel trophoblast regulators. We referenced our data to those of similar genetic screens performed in cancer cell lines and primed human pluripotent stem cells (hPSCs), as well as gene expression data of the early human embryos, to identify potential hTSC-specific and -enriched regulators. Among those are TEAD1, a gene previously reported to be dispensable for mouse placentation6. However, in the human trophoblast context, TEAD1 targets many hTSC regulators and plays a major role in its specification and maintenance. Overall, our study presents the first CRISPR/Cas9 knockout screen in a human extraembryonic lineage and provides a valuable resource for future trophoblast research.

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

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

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Conversion of Fibroblasts into Functional Trophoblast Stem-like Cells

Project description:Here we demonstrate the generation of stable induced trophoblast stem cells (iTSCs) from fibroblasts by the transient expression of Gata3, Eomes and Tfap2c. Transcriptome and methylome analyses and functional assays such as hemorrhagic lesion formation and placenta contribution suggested a high degree of conversion. Careful examination of the reprogramming process indicated that the cells did not go through a transient pluripotent state. Detect and compare different H2A.X deposition patterns in ES cells,MEFs and iTSC and TS cells, with Illumina HiSeq 2000

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

Project description:Naïve human pluripotent stem cells (hPSCs) provide a unique experimental platform of cell fate decisions during pre-implantation development, but their lineage potential remains incompletely characterized. As naïve hPSCs share transcriptional and epigenomic signatures with trophoblast cells, it has been proposed that the naïve state may have enhanced predisposition for differentiation along this extraembryonic lineage. Here we examined the trophoblast potential of isogenic naïve and primed hPSCs. We found that naïve hPSCs can directly give rise to human trophoblast stem cells (hTSCs) and undergo further differentiation into both extravillous and syncytiotrophoblast. In contrast, primed hPSCs do not support hTSC derivation, but give rise to non-self-renewing cytotrophoblasts in response to BMP4. Global transcriptome and chromatin accessibility analyses indicate that hTSCs derived from naïve hPSCs acquire features of pre-implantation trophectoderm. The derivation of hTSCs from naïve hPSCs will enable elucidation of early mechanisms that govern normal human trophoblast development and associated pathologies.

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