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Delamination of trophoblast-like syncytia from the amniotic ectodermal analogue in human primed embryonic stem cell-based differentiation model.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE175980 | GEO | 2022/06/21

REPOSITORIES: GEO

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Project description:The embryonic ectoderm is composed of four domains: neural plate, neural crest, pre-placodal region (PPR) and epidermis. Their formation is initiated during early gastrulation by dorsal-ventral and anterior-posterior gradients of signaling factors that first divide the embryonic ectoderm into neural and non-neural domains. Next, the neural crest and PPR domains arise, either via differential competence of the neural and non-neural ectoderm (binary competence model) or via interactions between the neural and non-neural ectoderm tissues to produce an intermediate neural border zone (NB) (border state model) that subsequently separates into neural crest and PPR. Many previous gain- and loss-of-function experiments demonstrate that numerous TFs are expressed in initially overlapping zones that gradually resolve into patterns that by late neurula stages are characteristic of each of the four domains. Several of these studies suggested that this is accomplished by a combination of repressive TF interactions and competence to respond to local signals. In this study, we ectopically expressed TFs that at neural plate stages are characteristic of one domain in a different domain to test whether they act cell autonomously as repressors. We found that almost all tested TFs caused reduced expression of the other TFs. At gastrulation these effects were strictly within the lineage-labeled cells, indicating that the effects were cell autonomous, i.e., due to TF interactions within individual cells. Analysis of previously published single cell RNAseq datasets showed that at the end of gastrulation, and continuing to neural tube closure stages, many ectodermal cells express TFs characteristic of more than one neural plate stage domain, indicating that different TFs have the opportunity to interact within the same cell. At neurula stages repression was observed both in the lineage-labeled cells and in adjacent cells not bearing detectable lineage label, suggesting that cell-to-cell signaling has begun to contribute to the separation of the domains. Together, these observations directly demonstrate previous suggestions in the literature that the segregation of embryonic ectodermal domains initially involves cell autonomous, repressive TF interactions within an individual cell followed by the subsequent advent of non-cell autonomous signaling to neighbors.

Project description:BackgroundPluripotency is proposed to exist in two different stages: Naive and Primed. Conventional human pluripotent cells are essentially in the primed stage. In recent years, several protocols have claimed to generate naive human embryonic stem cells (hESCs). To the best of our knowledge, none of these protocols is currently recognized as the gold standard method. Furthermore, the consistency of the resulting cells from these diverse protocols at the molecular level is yet to be shown. Additionally, little is known about the principles that govern the metabolic differences between naive and primed pluripotency. In this work, using a computational approach, we tried to shed light on these basic issues.ResultsWe showed that, after batch effect removal, the transcriptome data of eight different protocols which supposedly produce naive hESCs are clustered consistently when compared to the primed ones. Next, by integrating transcriptomes of all hESCs obtained by these protocols, we reconstructed p-hESCNet and n-hESCNet, the first metabolic network models representing hESCs. By exploiting reporter metabolite analysis we showed that the status of NAD + and the metabolites involved in the TCA cycle are significantly altered between naive and primed hESCs. Furthermore, using flux variability analysis (FVA), the models showed that the kynurenine-mediated metabolism of tryptophan is remarkably downregulated in naive human pluripotent cells.ConclusionThe aim of the present paper is twofold. Firstly, our findings confirm the applicability of all these protocols for generating naive hESCs, due to their consistency at the transcriptome level. Secondly, we showed that in silico metabolic models of hESCs can be used to simulate the metabolic states of naive and primed pluripotency. Our models confirmed the OXPHOS activation in naive cells and showed that oxidation-reduction potential vary between naive and primed cells. Tryptophan metabolism is also outlined as a key pathway in primed pluripotency and the models suggest that decrements in the activity of this pathway might be an appropriate marker for naive pluripotency.

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Delamination of trophoblast-like syncytia from the amniotic ectodermal analogue in human primed embryonic stem cell-based differentiation model.

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