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 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 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.

Derivation of human trophoblast stem cells from human pluripotent stem cells

Placenta ◽  
2019 ◽  
Vol 83 ◽  
pp. e59
Author(s):  
Adam Mischler ◽  
Victoria Karakis ◽  
Adriana San Miguel ◽  
Balaji Rao
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Human Pluripotent Stem Cells ◽  
Human Trophoblast ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem

scholarly journals Pluripotency-Independent Induction of Human Trophoblast Stem Cells from Fibroblasts

2021 ◽  
Author(s):  
Yosef Buganim ◽  
Moriyah Naama ◽  
Ahmed Radwan ◽  
Valery Zayat ◽  
Shulamit Sebban ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem ◽  
Gene Signature ◽  
Chromatin Accessibility ◽  
Double Knockout ◽  
Human Trophoblast ◽  
Trophoblast Stem Cells ◽  
Pluripotent State ◽  
Trophoblast Stem ◽  
Specific Factors

Recent studies demonstrated that human trophoblast stem-like cells (hTS-like cells) can be derived from naive embryonic stem cells or be induced from somatic cells by the pluripotency factors, OSKM. This raises two main questions; (i) whether human induced TSCs (hiTSCs) can be generated independently to pluripotent state or factors and (ii) what are the mechanisms by which hTSC state is established during reprogramming. Here, we identify GATA3, OCT4, KLF4 and MYC (GOKM) as a pluripotency-independent combination of factors that can generate stable and functional hiTSCs, from both male and female fibroblasts. By using single and double knockout (KO) fibroblasts for major pluripotency genes (i.e. SOX2 or NANOG/PRDM14) we show that GOKM not only is capable of generating hiTSCs from the KO cells, but rather that the efficiency of the process is increased. Through H3K4me2 and chromatin accessibility profiling we demonstrate that GOKM target different loci and genes than OSKM, and that a significant fraction of them is related to placenta and trophoblast function. Moreover, we show that GOKM exert a greater pioneer activity compared to OSKM. While GOKM target many specific hTSC loci, OSKM mainly target hTSC loci that are shared with hESCs. Finally, we reveal a gene signature of trophoblast-related genes, consisting of 172 genes which are highly expressed in blastocyst-derived TSCs and GOKM-hiTSCs but absent or mildly expressed in OSKM-hiTSCs. Taken together, these results imply that not only is the pluripotent state, and SOX2 specifically, not required to produce functional hiTSCs, but that pluripotency-specific factors actually interfere with the acquisition of the hTSC state during reprogramming.

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 Two distinct trophectoderm lineage stem cells from human pluripotent stem cells

2019 ◽  
Author(s):  
Adam Mischler ◽  
Victoria Karakis ◽  
Jessica Mahinthakumar ◽  
Celeste Carberry ◽  
Adriana San Miguel ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Pluripotent Stem Cells ◽  
Fetal Tissue ◽  
Human Pluripotent Stem Cells ◽  
Placental Development ◽  
Human Trophoblast ◽  
Trophoblast Stem Cells ◽  
Distinct Cell ◽  
Additional Cell

SummaryTrophoblasts are the principal cell type of the placenta. The use of human trophoblast stem cells (hTSCs) as a model for studies of early placental development is hampered by limited genetic diversity of existing hTSC lines, and constraints on using human fetal tissue or embryos needed to generate additional cell lines. Here we report the derivation of two distinct stem cells of the trophectoderm lineage from human pluripotent stem cells. The first is a CDX2- stem cell equivalent to primary hTSCs – they both exhibit identical expression of key markers, are maintained in culture and differentiate under similar conditions, and share high transcriptome similarity. The second is a CDX2+ putative human trophectoderm stem cell (hTESC) with distinct cell culture requirements and differences in gene expression and differentiation relative to hTSCs. Derivation of hTSCs and hTESCs from pluripotent stem cells significantly enables construction of models for normal and pathological placental development.

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.

scholarly journals Induction of Human Trophoblast Stem Cells from Somatic Cells and Pluripotent Stem Cells

Cell Reports ◽  
2020 ◽  
Vol 33 (8) ◽  
pp. 108419
Author(s):  
Gaël Castel ◽  
Dimitri Meistermann ◽  
Betty Bretin ◽  
Julie Firmin ◽  
Justine Blin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Somatic Cells ◽  
Human Trophoblast ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem

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 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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