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 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.

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

2020 ◽  
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

scholarly journals SIP1 Mediates Cell-Fate Decisions between Neuroectoderm and Mesendoderm in Human Pluripotent Stem Cells

2010 ◽  
Vol 6 (1) ◽  
pp. 59-70 ◽  
Author(s):  
Zhenzhi Chng ◽  
Adrian Teo ◽  
Roger A. Pedersen ◽  
Ludovic Vallier
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Human Pluripotent Stem Cells ◽  
Cell Fate Decisions

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 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 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 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 SUMO maintains the chromatin environment of human induced pluripotent stem cells

2020 ◽  
Author(s):  
Barbara Mojsa ◽  
Michael H. Tatham ◽  
Lindsay Davidson ◽  
Magda Liczmanska ◽  
Jane E. Wright ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Transcriptional Start Site ◽  
Chromatin Accessibility ◽  
Covalent Attachment ◽  
Cell Fate Decisions ◽  
Sumo Modification ◽  
Induced Pluripotent

AbstractPluripotent stem cells represent a powerful system to identify the mechanisms governing cell fate decisions during early mammalian development. Covalent attachment of the Small Ubiquitin Like Modifier (SUMO) to proteins has emerged as an important factor in stem cell maintenance. Here we show that SUMO is required to maintain stem cells in their pluripotent state and identify many chromatin-associated proteins as bona fide SUMO substrates in human induced pluripotent stem cells (hiPSCs). Loss of SUMO increases chromatin accessibility and expression of long non-coding RNAs and human endogenous retroviral elements, indicating a role for the SUMO modification of SETDB1 and a large TRIM28 centric network of zinc finger proteins in silencing of these elements. While most protein coding genes are unaffected, the Preferentially Expressed Antigen of Melanoma (PRAME) gene locus becomes more accessible and transcription is dramatically increased after inhibition of SUMO modification. When PRAME is silent, a peak of SUMO over the transcriptional start site overlaps with ChIP-seq peaks for cohesin, RNA pol II, CTCF and ZNF143, with the latter two heavily modified by SUMO. These associations suggest that silencing of the PRAME gene is maintained by the influence of SUMO on higher order chromatin structure. Our data indicate that SUMO modification plays an important role in hiPSCs by repressing genes that disrupt pluripotency networks or drive differentiation.

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