In vitro attachment and symmetry breaking of a human embryo model assembled from primed pluripotent stem cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE202542 | GEO | 2022/06/02
REPOSITORIES: GEO
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Project description:In vitro attachment and symmetry breaking of a human embryo model assembled from primed pluripotent stem cells
| PRJNA836533 | ENA
Project description:The human embryo undergoes morphogenetic transformations following implantation into the uterus and yet our knowledge of this crucial stage is limited by the inability to observe the embryo in vivo. Here, we establish a stem cell-derived human post-implantation embryo model comprised of embryonic and extraembryonic tissues. Overexpression of the transcription factors GATA6 and SOX17 or GATA3 and AP2g in hESCs allowed us to generate hypoblast-like and trophoblast-like cells, respectively. We established conditions to combine these extraembryonic-like cells with wildtype embryonic stem cells and promote their self-organization into structures that mimic aspects of the post-implantation human embryo. These aggregates contain an inner pluripotent epiblast-like domain surrounded by both hypoblast- and trophoblast-like tissues. We show that this human embryo stem cell model robustly generates several cell types, including amnion-, extraembryonic mesenchyme- and primordial germ cell-like cells. Using perturbation experiments, we demonstrated that these populations arise in response to BMP signaling. This model also allowed us to identify an inhibitory role for SOX17 in the specification of anterior hypoblast-like cells. Modulation of the subpopulations in the hypoblast-like compartment demonstrated that these extraembryonic-like cells impact epiblast-like domain differentiation, highlighting functional tissue-tissue crosstalk. In conclusion, this modular, tractable model of the human embryo that includes both embryonic- and extraembryonic-like cells has the potential to probe key questions of human post-implantation development.
2023-06-14 | GSE218314 | GEO
Project description:The human embryo breaks symmetry to form the anterior-posterior axis of the body. As the embryo elongates along this axis, progenitors in the tailbud give rise to tissues that generate the spinal cord, skeleton, and musculature. This raises the question of how the embryo achieves axial elongation and patterning. While ethics necessitate in vitro studies, the variability of organoid systems has hindered mechanistic insights. Here we developed a bioengineering and machine learning framework that optimizes symmetry breaking by tuning the spatial coupling between human stem cell-derived organoids. This framework enabled the reproducible generation of axially elongating organoids, each possessing a tailbud and neural tube. We discovered that an excitable system composed of WNT/FGF signaling drives elongation through induction of a neuromesodermal progenitor (NMP)-like signaling center. We discovered that instabilities in the excitable system are suppressed by secreted WNT inhibitors. Absence of these inhibitors led to ectopic tailbuds and branches. Our results identify mechanisms governing stable human axial elongation.
2022-12-12 | GSE220472 | GEO
Project description:Induction of the Arf tumor suppressor in response to hyperproliferative stress following oncogene activation activates a p53-dependent transcriptional program that limits the expansion of incipient cancer cells. Although Arf is not expressed in most tissues of fetal or young adult mice, it is physiologically expressed in the fetal yolk sac, a tissue derived from the extraembryonic endoderm. We demonstrate that expression of the mouse p19Arf protein marks late stages of extraembryonic endoderm differentiation in cultured embryoid bodies derived from either embryonic stem cells or induced pluripotent stem cells, and that Arf inactivation specifically delays the differentiation of the extraembryonic endoderm lineage, but not the formation of other germ cell lineages from pluripotent progenitors. Arf is required for the timely induction of extraembryonic endodermal cells in response to Ras/Erk signaling and, in turn, acts through p53 to ensure extraembryonic endoderm lineage development, but not maintenance. Remarkably, a significant temporal delay in extraembryonic endoderm differentiation detected during the maturation of Arf-null embryoid bodies is rescued by enforced expression of miR-205, a micro-RNA up-regulated by p19Arf and p53. Introduction of miR-205 into Arf-null embryonic stem cells rescues defective ExEn formation and elicits a program of gene expression that controls the migration and adhesion of embryonic endodermal cells. This occurs, at least in part, through atypical regulation of genes that control the epithelial-to-mesenchymal transition in cancer cells. Our findings suggest that noncanonical and canonical roles of Arf in extraembryonic endoderm development and tumor suppression, respectively, may be conceptually linked through mechanisms that govern cell-to-cell attachment and migration. 4 samples total two each at two time points in ESC development At each time point one sample was treted with miR-205 and the other with a GFP control vector
2013-04-01 | E-GEOD-42210 | biostudies-arrayexpress
Project description:Embryonic (ES) and epiblast (EpiSC) stem cells are pluripotent but committed to an embryonic lineage fate. Conversely, trophoblast (TS) a nd extraembryonic endoderm (XEN) stem cells contribute predominantly to tissues of the placenta and yolk sac, respectively. Here we show that each of these four stem cell types is defined by a unique DNA methylation profile. Despite their distinct developmental origin, TS and XEN cells share key epigenomic hallmarks, chiefly characterized by robust DNA methylation of embryo-specific developmental regulators, as well as a subordinate role of 5-hydroxymethylation. We also observe a substantial methylation reinforcement of pre-existing epigenetic repressive marks that specifically occurs in extraembryonic stem cells compared to in vivo tissue, presumably due to continued high Dnmt3b expression levels. These differences establish a major epigenetic barrier between the embryonic and extraembryonic stem cell types. In addition, epigenetic lineage boundaries also separate the two extraembryonic stem cell types by mutual repression of key lineage-specific transcription factors. Thus, global DNA methylation patterns are a defining feature of each stem cell type that underpin lineage commitment and differentiative potency of early embryo-derived stem cells. Our detailed methylation profiles identify a cohort of developmentally regulated sequence elements, such as orphan CpG islands, that will be most valuable to uncover novel transcriptional regulators and pivotal M-^QM-^QgatekeeperM-^RM-^R genes in pluripotency and lineage differentiation.
2013-07-03 | E-MTAB-1754 | biostudies-arrayexpress
Project description:Hypoblast stem cells were derived from rat embryonic stem cells (rESCs) by culturing with LIF, EGF, PDGF, and 2% fetal bovine serum. mRNA expression profiles of the cells during derivation at different time points were determined with Affymetrix microarrays. Global transcriptome of rESC-derived hypoblast stem cells (cHypoSCs) was similar to that of rat embryo-derived hypoblast stem cells and rat multipotent adult progenitor cells. In addition, the transcriptome of these cells were compared with the previously published datasets including transcriptome of mouse embryonic stem cells, extraembryonic endoderm cells, single cells of mouse embryos (E3.25, E3.5, and E4.5). The comparison revealed that cHypoSCs have the transcriptome similar to that of extraembryonic endoderm cells and E3.5 primitive endoderm cells.
2019-01-01 | GSE104697 | GEO
Project description:Bivalent histone domains have been proposed to contribute to pluripotency in embryonic stem cells, suggesting an epigenetic mechanism may regulate stem cell behavior in general. Here we compare histone modifications in two other stem cells derived from the blastocyst. We show that extraembryonic stem cells have little repressive lysine 27 trimethylation and few bivalent domains. Thus, bivalent domains are not a common mechanism for maintaining the undifferentiated state in blastocyst-derived stem cells and alternative mechanisms must mediate transcriptional repression in extraembryonic cells. We show that lysine 9 trimethylation, but not DNA methylation, is likely to fulfill this role. Intriguingly, although we do detect bivalent domains in pluripotent cells in the early mouse embryo, the epigenetic status of extraembryonic cells does not entirely reflect their in vitro stem cell counterparts. Therefore, differences in epigenetic regulation between lineage progenitors in vivo and in vitro may arise during selection for self-renewal in vitro. Expression profiles [GSM388878-GSM388881] of three different stem cells (R1 embryonic stem cells, trophoblast stem cells, extraembryonic endoderm stem cells) were generated for comparison to CHIP-seq data [GSM392044-GSM392055] of the same three stem cell lines to observe correlations with Histone 3 K4 and K27 trimethylation patterns. CHIP-seq details: R1 embryonic stem cells, trophoblast stem cells or extraembryonic endoderm stem cells were grown, lysed and chromatin purified. The chromatin was immunoprecipitated for either histone 3 K4 trimethylation or histone 3 K27 trimethylation and the immunoprecipitate was subjected to purification and high-throughput Illumina-based sequencing.
2010-05-16 | E-GEOD-15519 | biostudies-arrayexpress
Project description:Embryo-like structures generated from stem cells can achieve varying developmental milestones, but none have been shown to progress through gastrulation, neurulation, and organogenesis. Here, we show that "ETiX" mouse embryoids, assembled from embryonic stem cells, trophoblast stem cells and inducible extraembryonic endoderm stem cells, can develop into gastrulating embryoids, and beyond to generate neurulating embryoids, which generate the progenitors needed to create the entire organism. The head-folds of ETiX neurulating embryoids show anterior expression of Otx2, defining forebrain and midbrain regions that resemble those of the natural mouse embryo. Neurulating embryoids also develop beating heart-like structures, trunks comprising a neural tube and somites, tail buds containing neuromesodermal progenitors and primordial germ cells, and gut tubes derived from definitive endoderm. Notably, neurulating embryoids also develop a yolk sac with blood islands. Overall, ETiX neurulating embryoid formation strongly resembles natural embryogenesis, advancing embryo-like development further than any other stem-cell derived model and within extra-embryonic membranes.
2022-08-12 | GSE209792 | GEO
Project description:Blastocyst-derived stem cell lines were shown to self-organize into embryo-like structures in 3D cell culture environments. Here, we provide evidence that embryo-like structures can be generated solely based on transcription factor-mediated reprogramming of embryonic stem cells in a simple 3D co-culture system. Embryonic stem cells in these cultures self-organize into elongated, compartmentalized embryo-like structures reflecting aspects of the inner regions of the early post-implantation embryo. Single-cell RNA-seq reveals transcriptional profiles resembling epiblast, primitive-/visceral endoderm, and extraembryonic ectoderm of early murine embryos around E4.5–E5.5. In this stem cell-based embryo model, progression from rosette formation to lumenogenesis accompanied by progression from naïve- to primed pluripotency was observed within Epi-like cells. Additionally, lineage specification of primordial germ cells and distal/anterior visceral endoderm-like cells was observed in epiblast- or visceral endoderm-like compartments, respectively. The system presented in this study allows for fast and reproducible generation of embryo-like structures, providing an additional tool to study aspects of early embryogenesis.
2021-11-15 | GSE188394 | GEO
Project description:Bivalent histone domains have been proposed to contribute to pluripotency in embryonic stem cells, suggesting an epigenetic mechanism may regulate stem cell behavior in general. Here we compare histone modifications in two other stem cells derived from the blastocyst. We show that extraembryonic stem cells have little repressive lysine 27 trimethylation and few bivalent domains. Thus, bivalent domains are not a common mechanism for maintaining the undifferentiated state in blastocyst-derived stem cells and alternative mechanisms must mediate transcriptional repression in extraembryonic cells. We show that lysine 9 trimethylation, but not DNA methylation, is likely to fulfill this role. Intriguingly, although we do detect bivalent domains in pluripotent cells in the early mouse embryo, the epigenetic status of extraembryonic cells does not entirely reflect their in vitro stem cell counterparts. Therefore, differences in epigenetic regulation between lineage progenitors in vivo and in vitro may arise during selection for self-renewal in vitro.
2010-05-17 | GSE15519 | GEO