Rapid generation of murine haploid-induced trophoblast stem cells via a Tet-on system

AbstractTrophoblast stem cell (TSC) is crucial to the formation of placenta in mammals. Histone demethylase JMJD2 (also known as KDM4) family proteins have been previously shown to support self-renewal and differentiation of stem cells. However, their roles in the context of the trophoblast lineage remain unclear. Here, we find that knockdown of Jmjd2b resulted in differentiation of TSCs, suggesting an indispensable role of JMJD2B/KDM4B in maintaining the stemness. Through the integration of transcriptome and ChIP-seq profiling data, we show that JMJD2B is associated with a loss of H3K36me3 in a subset of embryonic lineage genes which are marked by H3K9me3 for stable repression. By characterizing the JMJD2B binding motifs and other transcription factor binding datasets, we discover that JMJD2B forms a protein complex with AP-2 family transcription factor TFAP2C and histone demethylase LSD1. The JMJD2B–TFAP2C–LSD1 complex predominantly occupies active gene promoters, whereas the TFAP2C–LSD1 complex is located at putative enhancers, suggesting that these proteins mediate enhancer–promoter interaction for gene regulation. We conclude that JMJD2B is vital to the TSC transcriptional program and safeguards the trophoblast cell fate via distinctive protein interactors and epigenetic targets.

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Inactivation of Lsd1 triggers senescence in trophoblast stem cells by induction of Sirt4

Cell Death and Disease ◽

10.1038/cddis.2017.48 ◽

2017 ◽

Vol 8 (2) ◽

pp. e2631-e2631 ◽

Cited By ~ 15

Author(s):

Josefina Castex ◽

Dominica Willmann ◽

Toufike Kanouni ◽

Laura Arrigoni ◽

Yan Li ◽

...

Keyword(s):

Stem Cells ◽

Trophoblast Stem Cells ◽

Trophoblast Stem

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Derivation of macaque trophoblast stem cells

10.1101/2020.03.17.995407 ◽

2020 ◽

Author(s):

Jenna Kropp Schmidt ◽

Michael G. Meyer ◽

Gregory J. Wiepz ◽

Lindsey N. Block ◽

Brittany M. Dusek ◽

...

Keyword(s):

Stem Cells ◽

Culture Media ◽

Syncytium Formation ◽

First Trimester ◽

Gonadotropin Secretion ◽

Trophoblast Stem Cells ◽

Trophoblast Stem ◽

Mhc Class I Molecule

AbstractNonhuman primates are excellent models for studying human placentation as experimental manipulations in vitro can be translated to in vivo pregnancy. Our objective was to develop macaque trophoblast stem cells (TSC) as an in vitro platform for future assessment of primate trophoblast development and function. Macaque TSC lines were generated by isolating first trimester placental villous cytotrophoblasts followed by culture in TSC medium to “reprogram” the cells to a proliferative state. TSCs grew as mononuclear colonies, whereas upon induction of syncytiotrophoblast (ST) differentiation multinuclear structures appeared, indicative of syncytium formation. Chorionic gonadotropin secretion was >4,000-fold higher in ST culture media compared to TSC media. Characteristic trophoblast hallmarks were defined in TSCs and ST including expression of C19MC miRNAs and macaque placental nonclassical MHC class I molecule, Mamu-AG. TSC differentiation to extravillous trophoblasts (EVTs) with or without the ALK-5 inhibitor A83-01 resulted in differing morphologies but similar expression of Mamu-AG and CD56 as assessed by flow cytometry, hence further refinement of relevant EVT markers is needed. Our preliminary characterization of macaque TSCs suggests that these cells represent a proliferative, self-renewing TSC population capable of differentiating to STs in vitro thereby establishing an experimental model of primate placentation.

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Author response: Derivation of trophoblast stem cells from naïve human pluripotent stem cells

10.7554/elife.52504.sa2 ◽

2020 ◽

Cited By ~ 2

Author(s):

Chen Dong ◽

Mariana Beltcheva ◽

Paul Gontarz ◽

Bo Zhang ◽

Pooja Popli ◽

...

Keyword(s):

Stem Cells ◽

Pluripotent Stem Cells ◽

Human Pluripotent Stem Cells ◽

Author Response ◽

Trophoblast Stem Cells ◽

Trophoblast Stem

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Super Enhancer Profiles Identify Key Cell Identity Genes During Differentiation From Embryonic Stem Cells to Trophoblast Stem Cells Super Enhencers in Trophoblast Differentiation

Frontiers in Genetics ◽

10.3389/fgene.2021.762529 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rongpu Jia ◽

Yu Gao ◽

Song Guo ◽

Si Li ◽

Liangji Zhou ◽

...

Keyword(s):

Stem Cells ◽

Embryo Implantation ◽

Control Cell ◽

Embryonic Stem ◽

Growth Factor Receptor ◽

Chromatin Accessibility ◽

Integrated Analysis ◽

Cell Identity ◽

Trophoblast Stem Cells ◽

Trophoblast Stem

Trophoblast stem cells (TSCs) are derived from blastocysts and the extra-embryonic ectoderm (ExE) of post-implantation embryos and play a significant role in fetal development, but the roles that TSCs play in the earlier status of fetal diseases need further exploration. Super enhancers (SEs) are dense clusters of stitched enhancers that control cell identity determination and disease development and may participate in TSC differentiation. We identified key cell identity genes regulated by TSC-SEs via integrated analysis of H3K27ac and H3K4me1 chromatin immunoprecipitation sequencing (ChIP-seq), RNA-sequencing (RNA-seq) and ATAC-sequencing (ATAC-seq) data. The identified key TSC identity genes regulated by SEs, such as epidermal growth factor receptor (EGFR), integrin β5 (ITGB5) and Paxillin (Pxn), were significantly upregulated during TSC differentiation, and the transcription network mediated by TSC-SEs enriched in terms like focal adhesion and actin cytoskeleton regulation related to differentiation of TSCs. Additionally, the increased chromatin accessibility of the key cell identity genes verified by ATAC-seq further demonstrated the regulatory effect of TSC-SEs on TSC lineage commitment. Our results illustrated the significant roles of the TSC-SE-regulated network in TSC differentiation, and identified key TSC identity genes EGFR, ITGB5 and Pxn, providing novel insight into TSC differentiation and lays the foundation for future studies on embryo implantation and related diseases.

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