Connexin31-deficient trophoblast stem cells: a model to analyze the role of gap junction communication in mouse placental development

AbstractThe majority of placental pathologies are associated with failures in trophoblast differentiation, yet the underlying transcriptional regulation is poorly understood. Here, we use human trophoblast stem cells to elucidate the function of the transcription factor MSX2 in trophoblast specification. We show that depletion of MSX2 de-represses the syncytiotrophoblast program, while forced expression of MSX2 blocks it. We demonstrate that a large proportion of the affected genes are directly bound and regulated by MSX2 and identify components of the SWI/SNF complex as its strong interactors. Our findings uncover the pivotal role of MSX2 in cell fate decisions that govern human placental development and function.

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Skp2 contributes to cell cycle progression in trophoblast stem cells and to placental development

Genes to Cells ◽

10.1111/gtc.12769 ◽

2020 ◽

Vol 25 (6) ◽

pp. 427-438 ◽

Cited By ~ 1

Author(s):

Yuhei Yamauchi ◽

Akihiro Nita ◽

Masaaki Nishiyama ◽

Yoshiharu Muto ◽

Hideyuki Shimizu ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Cell Cycle Progression ◽

Placental Development ◽

Cycle Progression ◽

Trophoblast Stem Cells ◽

Trophoblast Stem

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A Critical Role of TET1/2 Proteins in Cell-Cycle Progression of Trophoblast Stem Cells

Stem Cell Reports ◽

10.1016/j.stemcr.2018.02.014 ◽

2018 ◽

Vol 10 (4) ◽

pp. 1355-1368 ◽

Cited By ~ 16

Author(s):

Stephanie Chrysanthou ◽

Claire E. Senner ◽

Laura Woods ◽

Elena Fineberg ◽

Hanneke Okkenhaug ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Cell Cycle Progression ◽

Critical Role ◽

Cycle Progression ◽

Trophoblast Stem Cells ◽

Trophoblast Stem

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Efficient derivation of human trophoblast stem cells from primed pluripotent stem cells

Science Advances ◽

10.1126/sciadv.abf4416 ◽

2021 ◽

Vol 7 (33) ◽

pp. eabf4416

Author(s):

Yanxing Wei ◽

Tianyu Wang ◽

Lishi Ma ◽

Yanqi Zhang ◽

Yuan Zhao ◽

...

Keyword(s):

Stem Cells ◽

Pluripotent Stem Cells ◽

Chromatin Accessibility ◽

Placental Development ◽

Differentiation Potential ◽

Human Trophoblast ◽

Trophoblast Stem Cells ◽

Trophoblast Stem ◽

Early Placenta ◽

And Function

Human trophoblast stem cells (hTSCs) provide a valuable model to study placental development and function. While primary hTSCs have been derived from embryos/early placenta, and transdifferentiated hTSCs from naïve human pluripotent stem cells (hPSCs), the generation of hTSCs from primed PSCs is problematic. We report the successful generation of TSCs from primed hPSCs and show that BMP4 substantially enhances this process. TSCs derived from primed hPSCs are similar to blastocyst-derived hTSCs in terms of morphology, proliferation, differentiation potential, and gene expression. We define the chromatin accessibility dynamics and histone modifications (H3K4me3/H3K27me3) that specify hPSC-derived TSCs. Consistent with low density of H3K27me3 in primed hPSC-derived hTSCs, we show that knockout of H3K27 methyltransferases (EZH1/2) increases the efficiency of hTSC derivation from primed hPSCs. Efficient derivation of hTSCs from primed hPSCs provides a simple and powerful model to understand human trophoblast development, including the pathogenesis of trophoblast-related disorders, by generating disease-specific hTSCs.

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Isolation and characterisation of a novel trophoblast side-population from first trimester placentae

Reproduction ◽

10.1530/rep-14-0646 ◽

2015 ◽

Vol 150 (5) ◽

pp. 449-462 ◽

Cited By ~ 22

Author(s):

J L James ◽

D G Hurley ◽

T K J B Gamage ◽

T Zhang ◽

R Vather ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Side Population ◽

First Trimester ◽

Placental Development ◽

Human Trophoblast ◽

Trophoblast Stem Cells ◽

Trophoblast Stem ◽

Future Work ◽

Extravillous Trophoblasts

The placenta is responsible for all nutrient and gas exchange between mother and baby during pregnancy. The differentiation of specialised placental epithelial cells called trophoblasts is essential for placental function, but we understand little about how these populations arise. Mouse trophoblast stem cells have allowed us to understand many of the factors that regulate murine trophoblast lineage development, but the human placenta is anatomically very different from the mouse, and it is imperative to isolate a human trophoblast stem cell to understand human placental development. Here we have developed a novel methodology to isolate a Hoechst side-population of trophoblasts from early gestation placentae and compared their transcriptome to differentiated trophoblast populations (cytotrophoblasts and extravillous trophoblasts) using microarray technology. Side-population trophoblasts clustered as a transcriptomically distinct population but were more closely related to cytotrophoblasts than extravillous trophoblasts. Side-population trophoblasts up-regulated a number of genes characteristic of trophectoderm and murine trophoblast stem cells in comparison to cytotrophoblasts or extravillous trophoblasts and could be distinguished from both of these more mature populations by a unique set of 22 up-regulated genes, which were enriched for morphogenesis and organ development and the regulation of growth functions. Cells expressing two of these genes (LAMA2 and COL6A3) were distributed throughout the cytotrophoblast layer at the trophoblast/mesenchymal interface. Comparisons to previously published trophoblast progenitor populations suggest that the side-population trophoblasts isolated in this work are a novel human trophoblast population. Future work will determine whether these cells exhibit functional progenitor/stem cell attributes.

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The role of Smad4-dependent signaling in mouse trophoblast stem cells

Developmental Biology ◽

10.1016/j.ydbio.2011.05.331 ◽

2011 ◽

Vol 356 (1) ◽

pp. 214-215

Author(s):

Jiami Guo ◽

Padhmavathy Yuvaraj

Keyword(s):

Stem Cells ◽

Trophoblast Stem Cells ◽

Trophoblast Stem

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Zfp281 Shapes the Transcriptome of Trophoblast Stem Cells and Is Essential for Placental Development

Cell Reports ◽

10.1016/j.celrep.2019.04.028 ◽

2019 ◽

Vol 27 (6) ◽

pp. 1742-1754.e6 ◽

Cited By ~ 7

Author(s):

Takashi Ishiuchi ◽

Hiroaki Ohishi ◽

Tetsuya Sato ◽

Satoshi Kamimura ◽

Masayoshi Yorino ◽

...

Keyword(s):

Stem Cells ◽

Placental Development ◽

Trophoblast Stem Cells ◽

Trophoblast Stem

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Esrrb plays important roles in maintaining self-renewal of trophoblast stem cells (TSCs) and reprogramming somatic cells to induced TSCs

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjy054 ◽

2018 ◽

Vol 11 (6) ◽

pp. 463-473 ◽

Cited By ~ 1

Author(s):

Haibo Gao ◽

Rui Gao ◽

Linfeng Zhang ◽

Wenchao Xiu ◽

Ruge Zang ◽

...

Keyword(s):

Stem Cells ◽

Molecular Mechanisms ◽

Target Genes ◽

Cell Model ◽

Embryonic Stem ◽

Placental Development ◽

Self Renewal ◽

Trophoblast Stem Cells ◽

Trophoblast Stem

Abstract Trophoblast stem cells (TSCs), which can be derived from the trophoectoderm of a blastocyst, have the ability to sustain self-renewal and differentiate into various placental trophoblast cell types. Meanwhile, essential insights into the molecular mechanisms controlling the placental development can be gained by using TSCs as the cell model. Esrrb is a transcription factor that has been shown to play pivotal roles in both embryonic stem cell (ESC) and TSC, but the precise mechanism whereby Esrrb regulates TSC-specific transcriptome during differentiation and reprogramming is still largely unknown. In the present study, we elucidate the function of Esrrb in self-renewal and differentiation of TSCs, as well as during the induced TSC (iTSC) reprogramming. We demonstrate that the precise level of Esrrb is critical for stem state maintenance and further trophoblast differentiation of TSCs, as ectopically expressed Esrrb can partially block the rapid differentiation of TSCs in the absence of fibroblast growth factor 4. However, Esrrb depletion results in downregulation of certain key TSC-specific transcription factors, consequently causing a rapid differentiation of TSCs and these Esrrb-deficient TSCs lose the ability of hemorrhagic lesion formation in vivo. This function of Esrrb is exerted by directly binding and activating a core set of TSC-specific target genes including Cdx2, Eomes, Sox2, Fgfr4, and Bmp4. Furthermore, we show that Esrrb overexpression can facilitate the MEF-to-iTSC conversion. Moreover, Esrrb can substitute for Eomes to generate GEsTM-iTSCs. Thus, our findings provide a better understanding of the molecular mechanism of Esrrb in maintaining TSC self-renewal and during iTSC reprogramming.

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The Impact of Hypoxia in Early Pregnancy on Placental Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22189675 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9675

Author(s):

Hui Zhao ◽

Ronald J. Wong ◽

David K. Stevenson

Keyword(s):

Stem Cells ◽

First Trimester ◽

Low Oxygen ◽

Placental Development ◽

Trophoblast Stem Cells ◽

Oxygen Levels ◽

Trophoblast Stem ◽

Adverse Pregnancy ◽

And Function ◽

The Impact

Oxygen levels in the placental microenvironment throughout gestation are not constant, with severe hypoxic conditions present during the first trimester. This hypoxic phase overlaps with the most critical stages of placental development, i.e., blastocyst implantation, cytotrophoblast invasion, and spiral artery remodeling initiation. Dysregulation of any of these steps in early gestation can result in pregnancy loss and/or adverse pregnancy outcomes. Hypoxia has been shown to regulate not only the self-renewal, proliferation, and differentiation of trophoblast stem cells and progenitor cells, but also the recruitment, phenotype, and function of maternal immune cells. In this review, we will summarize how oxygen levels in early placental development determine the survival, fate, and function of several important cell types, e.g., trophoblast stem cells, extravillous trophoblasts, syncytiotrophoblasts, uterine natural killer cells, Hofbauer cells, and decidual macrophages. We will also discuss the cellular mechanisms used to cope with low oxygen tensions, such as the induction of hypoxia-inducible factor (HIF) or mammalian target of rapamycin (mTOR) signals, regulation of the metabolic pathway, and adaptation to autophagy. Understanding the beneficial roles of hypoxia in early placental development will provide insights into the root cause(s) of some pregnancy disorders, such as spontaneous abortion, preeclampsia, and intrauterine growth restriction.

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Role of autocrine bone morphogenetic protein Signaling in trophoblast stem cells

Biology of Reproduction ◽

10.1093/biolre/ioab213 ◽

2021 ◽

Author(s):

Jennie Au ◽

Daniela F Requena ◽

Hannah Rishik ◽

Sampada Kallol ◽

Chandana Tekkatte ◽

...

Keyword(s):

Stem Cells ◽

Bone Morphogenetic Protein ◽

Bmp Signaling ◽

Human Trophoblast ◽

Trophoblast Stem Cells ◽

Trophoblast Stem ◽

Morphogenetic Protein ◽

Bmp Pathway

Abstract The Bone Morphogenetic Protein (BMP) pathway is involved in numerous developmental processes, including cell growth, apoptosis, and differentiation. In mouse embryogenesis, BMP signaling is a well-known morphogen for both mesoderm induction and germ cell development. Recent evidence points to a potential role in development of the extra-embryonic compartment, including trophectoderm-derived tissues. In this study, we investigated the effect of BMP signaling in both mouse and human trophoblast stem cells (TSC) in vitro, evaluating the expression and activation of the BMP signaling response machinery, and the effect of BMP signaling manipulation during TSC maintenance and differentiation. Both mTSC and hTSC expressed various BMP ligands and the receptors BMPR1A and BMPR2, necessary for BMP response, and displayed maximal active BMP signaling when undifferentiated. We also observed a conserved modulatory role of BMP signaling during trophoblast differentiation, whereby maintenance of active BMP signaling blunted differentiation of TSC in both species. Conversely, the effect of BMP signaling on the undifferentiated state of TSC appeared to be species-specific, with SMAD-independent signaling important in maintenance of mTSC, and a more subtle role for both SMAD-dependent and -independent BMP signaling in hTSC. Altogether, these data establish an autocrine role for the BMP pathway in the trophoblast compartment. As specification and correct differentiation of the extra-embryonic compartment are fundamental for implantation and early placental development, insights on the role of the BMP signaling in early development might prove useful in the setting of in vitro fertilization as well as targeting trophoblast-associated placental dysfunction.

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