scholarly journals MSX2 safeguards syncytiotrophoblast fate of human trophoblast stem cells

2021 ◽  
Author(s):  
Ruth Hornbachner ◽  
Andreas Lackner ◽  
Sandra Haider ◽  
Martin Knöfler ◽  
Karl Mechtler ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Placental Development ◽  
Human Trophoblast ◽  
Trophoblast Stem Cells ◽  
Cell Fate Decisions ◽  
Trophoblast Stem ◽  
And Function ◽  
Strong Interactors

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.

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

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.

scholarly journals MSX2 safeguards syncytiotrophoblast fate of human trophoblast stem cells

2021 ◽  
Vol 118 (37) ◽  
pp. e2105130118
Author(s):  
Ruth Hornbachner ◽  
Andreas Lackner ◽  
Henrieta Papuchova ◽  
Sandra Haider ◽  
Martin Knöfler ◽  
...  
Keyword(s):  
Cell Fate ◽  
Target Gene ◽  
Cell Model ◽  
Placental Development ◽  
Human Trophoblast ◽  
Trophoblast Stem Cells ◽  
Cell Fate Decisions ◽  
Trophoblast Stem ◽  
Stem Cell Model ◽  
Trophoblast Stem Cell

Multiple placental pathologies are associated with failures in trophoblast differentiation, yet the underlying transcriptional regulation is poorly understood. Here, we discovered msh homeobox 2 (MSX2) as a key transcriptional regulator of trophoblast identity using the human trophoblast stem cell model. Depletion of MSX2 resulted in activation of the syncytiotrophoblast transcriptional program, while forced expression of MSX2 blocked it. We demonstrated that a large proportion of the affected genes were directly bound and regulated by MSX2 and identified components of the SWItch/Sucrose nonfermentable (SWI/SNF) complex as strong MSX2 interactors and target gene cobinders. MSX2 cooperated specifically with the SWI/SNF canonical BAF (cBAF) subcomplex and cooccupied, together with H3K27ac, a number of differentiation genes. Increased H3K27ac and cBAF occupancy upon MSX2 depletion imply that MSX2 prevents premature syncytiotrophoblast differentiation. Our findings established MSX2 as a repressor of the syncytiotrophoblast lineage and demonstrated its pivotal role in cell fate decisions that govern human placental development and disease.

scholarly journals Derivation of trophoblast stem cells from naïve human pluripotent stem cells

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chen Dong ◽  
Mariana Beltcheva ◽  
Paul Gontarz ◽  
Bo Zhang ◽  
Pooja Popli ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Chromatin Accessibility ◽  
Human Pluripotent Stem Cells ◽  
Human Trophoblast ◽  
Trophoblast Stem Cells ◽  
Cell Fate Decisions ◽  
Trophoblast Stem ◽  
Normal Human

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 are similar to blastocyst-derived hTSCs and acquire features of post-implantation trophectoderm. The derivation of hTSCs from naïve hPSCs will enable elucidation of early mechanisms that govern normal human trophoblast development and associated pathologies.

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

2004 ◽  
Vol 273 (1) ◽  
pp. 63-75 ◽  
Author(s):  
Mark Kibschull ◽  
Mariam Nassiry ◽  
Caroline Dunk ◽  
Alexandra Gellhaus ◽  
Jennifer A Quinn ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gap Junction ◽  
Placental Development ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Gap Junction Communication

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

Reproduction ◽  
2015 ◽  
Vol 150 (5) ◽  
pp. 449-462 ◽  
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.

scholarly journals The Impact of Hypoxia in Early Pregnancy on Placental Cells

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.

Role of autocrine bone morphogenetic protein Signaling in trophoblast stem cells

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.

scholarly journals Characterization of primary models of human trophoblast

Development ◽  
2021 ◽  
Author(s):  
Megan A. Sheridan ◽  
Xiaohui Zhao ◽  
Ridma C. Fernando ◽  
Lucy Gardner ◽  
Vicente Perez-Garcia ◽  
...  
Keyword(s):  
Stem Cells ◽  
Extravillous Trophoblast ◽  
Suitable Model ◽  
Placental Development ◽  
Human Trophoblast ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem

Although understanding of human placental development is still limited, two models, trophoblast organoids and trophoblast stem cells (TSC) provide new useful tools to study this. Both differentiate from villous cytotrophoblast (VCT) to either extravillous trophoblast (EVT) or syncytiotrophoblast (SCT). Here, we compare transcriptomes and miRNA profiles of these models to identify which trophoblast they resemble in vivo. Our findings indicate that TSC do not readily undergo SCT differentiation and closely resemble cells at the base of the cell columns from where EVT are derived. In contrast, organoids are similar to VCT and undergo spontaneous SCT differentiation. A defining feature of human trophoblast is that VCT and SCT are HLA null whilst EVT express HLA-C, -G, -E molecules. We find that trophoblast organoids retain these in vivo characteristics. In contrast, TSC do express classical HLA-A and HLA-B molecules and still maintain their expression after EVT differentiation with upregulation of HLA-G. Furthermore, HLA expression in TSC differs when grown in 3D rather than 2D suggesting mechanical cues are important. Our results will allow choice of the most suitable model to study trophoblast development, function and pathology.

scholarly journals Generation of human induced trophoblast stem cells

2020 ◽  
Author(s):  
Gaël Castel ◽  
Dimitri Meistermann ◽  
Betty Bretin ◽  
Julie Firmin ◽  
Justine Blin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
First Trimester ◽  
Alternative Methods ◽  
Extravillous Trophoblast ◽  
Human Embryos ◽  
List Type ◽  
Human Trophoblast ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem

SUMMARYHuman trophoblast stem cells (hTSC) derived from blastocysts and first-trimester cytotrophoblasts offer an unprecedented opportunity to study the human placenta. However, access to human embryos and first trimester placentas is limited thus preventing the establishment of hTSC from a variety of genetic backgrounds associated with placental disorders. In the present study, we show that hTSC can be generated from numerous genetic backgrounds using post-natal cells via two alternative methods: (I) somatic cell reprogramming of adult fibroblasts using the Yamanaka factors, and (II) cell fate conversion of naive and extended pluripotent stem cells. The resulted induced and converted hTSC (hiTSC/hcTSC) recapitulated hallmarks of hTSC including long-term self-renewal, expression of specific transcription factors, transcriptome-side signature, and the potential to differentiate into syncytiotrophoblast and extravillous trophoblast cells. We also clarified the developmental stage of hTSC and show that these cells resemble post-implantation NR2F2+ cytotrophoblasts (day 8-10). Altogether, hTSC lines of diverse genetics origins open the possibility to model both placental development and diseases in a dish.HighlightsReprogramming of human somatic cells to induced hTSC with OSKMConversion of naive and extended hPSC to hTSCGenetic diversity of hTSC linesDevelopmental matching of hTSC in the peri-implantation human embryo

scholarly journals Human trophoblast stem cells: Real or not real?

Placenta ◽  
2017 ◽  
Vol 60 ◽  
pp. S57-S60 ◽  
Author(s):  
Ching-Wen Chang ◽  
Mana M. Parast
Keyword(s):  
Stem Cells ◽  
Human Trophoblast ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem
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