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Hypoxia induces an early primitive streak signature, enhancing spontaneous elongation and lineage representation in gastruloids

ABSTRACT: The cellular microenvironment together with intrinsic regulators shapes stem cell identity and differentiation capacity. Mammalian early embryos are exposed to hypoxia in vivo and appear to benefit from hypoxic culture in vitro. Yet, how hypoxia influences stem cell transcriptional networks and lineage choices remain poorly understood. Here we investigated the molecular effects of acute and prolonged hypoxia on embryonic and extraembryonic stem cells as well as the functional impact on differentiation potential. We find a temporal and cell type-specific transcriptional response including an early primitive streak signature in hypoxic embryonic stem cells (ESCs) mediated by HIF1. Using a 3D gastruloid differentiation model, we show that hypoxia-induced T expression enables symmetry breaking and axial elongation in the absence of exogenous WNT activation. When combined with exogenous WNT activation, hypoxia enhances lineage representation in gastruloids, as demonstrated by highly enriched signatures of gut endoderm, notochord, neuromesodermal progenitors and somites. Our findings directly link the microenvironment to stem cell function and provide a rationale supportive of applying physiological conditions in models of embryo development.

ORGANISM(S): Mus musculus

PROVIDER: GSE195544 | GEO | 2022/08/24

REPOSITORIES: GEO

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Hypoxia induces an early primitive streak signature, enhancing spontaneous elongation and lineage representation in gastruloids

Project description:The cellular microenvironment together with intrinsic regulators shapes stem cell identity and differentiation capacity. Mammalian early embryos are exposed to hypoxia in vivo and appear to benefit from hypoxic culture in vitro. Yet, how hypoxia influences stem cell transcriptional networks and lineage choices remain poorly understood. Here we investigated the molecular effects of acute and prolonged hypoxia on embryonic and extraembryonic stem cells as well as the functional impact on differentiation potential. We find a temporal and cell type-specific transcriptional response including an early primitive streak signature in hypoxic embryonic stem cells (ESCs) mediated by HIF1. Using a 3D gastruloid differentiation model, we show that hypoxia-induced T expression enables symmetry breaking and axial elongation in the absence of exogenous WNT activation. When combined with exogenous WNT activation, hypoxia enhances lineage representation in gastruloids, as demonstrated by highly enriched signatures of gut endoderm, notochord, neuromesodermal progenitors and somites. Our findings directly link the microenvironment to stem cell function and provide a rationale supportive of applying physiological conditions in models of embryo development.

2022-08-24 | GSE178628 | GEO

Hypoxia induces an early primitive streak signature, enhancing spontaneous elongation and lineage representation in gastruloids

2022-08-24 | GSE195545 | GEO

Hypoxia induces a transcriptional early primitive streak signature in pluripotent cells enhancing spontaneous elongation and lineage representation in gastruloids [RNA-seq]

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Hypoxia induces a transcriptional primitive streak signature in ES cells and enhances lineage patterning in gastruloids

Project description:The cellular microenvironment shapes stem cell identity and differentiation capacity. Mammalian early embryos are exposed to hypoxia in vivo and benefit from hypoxic culture in vitro. Yet, how different components of the hypoxia response impact stem cell transcriptional networks and lineage choices remains unclear. Here we investigated the effect of acute and prolonged hypoxia on stem cell states and differentiation efficiencies of embryonic and extraembryonic cells. We show that prolonged hypoxia enhances differentiation of embryonic stem (ES) cells towards the mesendoderm lineage by transcriptionally priming cells with a primitive streak signature including Wnt3 and T expression. Exposure to hypoxia in ES culture or during formation of gastrulation-mimicking organoids (gastruloids) moderates T expression and enhances structural complexity. Hypoxic gastruloids generated without exogenous Wnt induction can spontaneously elongate and self-organize. Direct gene regulation by Hif1a, combined with DNA demethylation and metabolic rewiring modulate the transcriptional response and phenotypic outcome. Our findings highlight the influence of the microenvironment on stem cell function and provide a rationale supportive of applying physiological conditions in synthetic embryo models.

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Transcriptional Profiling of Hypoxic Neural Stem Cells to Identify Novel Regulators of Neural Stem Cell Biology

2015-07-30 | GSE68572 | GEO

Mature dendritic cells under hypoxic condition

Project description:Dendritic cells (DCs) are professional antigen-presenting cells whose activity is intrinsically linked to the microenvironment. Hypoxia is a condition of low oxygen tension occurring in inflammatory tissues that creates a special microenvironment conditioning cell physiology. We studied the effects of hypoxia on the differentiation of human monocytes into DCs and maturation into mature DCs. Mature DCs were differentiated in vitro from human monocytes under normoxic or hypoxic conditions and the gene expression profile was determined. The expression profile of mature dendritic cells under normoxia vs hypoxia was studied. Three healthy donors were used as biologial replicates.

2010-12-31 | E-GEOD-22282 | biostudies-arrayexpress

Wnt signalling sustains an EpiSCs subpopulation similar to primitive streak with increased mesendodermal potency

Project description:During gastrulation, epiblast cells are pluripotent and their fate is thought to be constrained principally by their position. Cell fate is progressively restricted by localised signalling cues from areas including the primitive streak (PS). However, it is unknown whether this restriction accompanies, at the single cell level, a reduction in potency. Investigation of these early transition events in vitro is possible via the use of Epiblast Stem Cells (EpiSCs), self-renewing pluripotent cell lines equivalent to the postimplantation epiblast. Strikingly, EpiSCs express various early lineage-specific markers in self-renewing conditions. However, it is unknown whether cells that express these markers are pluripotent, spontaneously differentiated, or biased towards specific lineages. Here we show that EpiSC are inherently heterogeneous and contain two major and mutually exclusive subpopulations with PS and neural characteristics respectively. Using differentiation assays and embryo grafting we demonstrate that PS-like EpiSCs are biased towards mesoderm and endoderm differentiation but they still retain their pluripotent character. The acquisition of a PS character by undifferentiated EpiSC is mediated by paracrine Wnt signalling. Elevation of Wnt activity promotes further restriction into PS-associated cell fates which occurs via the generation of distinct clonal mesendodermal and neuromesodermal precursors. Collectively, our data suggest that primed pluripotency encompasses a range of reversible lineage-biased states reflecting the birth of pioneer lineage precursors from a pool of uncommitted EpiSCs similar to the earliest cell fate restriction events taking place in the gastrula-stage epiblast. Total RNA obtained (3 biological replicates) from flow sorted dsRed2+, dsRed2-, and +CHIRON treated for 48h cells was isolated and labelled/amplified using the IlluminaM-BM-. TotalPrepM-bM-^DM-" RNA Amplification Kit (Life Technologies)

2014-03-04 | E-GEOD-48476 | biostudies-arrayexpress

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2008-06-15 | E-GEOD-6863 | biostudies-arrayexpress

Wnt signalling sustains an EpiSCs subpopulation similar to primitive streak with increased mesendodermal potency

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Transcriptional Profiling of Hypoxic Neural Stem Cells to Identify Novel Regulators of Neural Stem Cell Biology

Project description:Neural stem cells reside in a hypoxic microenvironment within the brain. However, the crucial transcription factors that regulate neural stem cell biology under physiologic hypoxia are poorly understood. Here, we have performed microarray analysis of hypoxic versus normoxic neural stem cells with the aim of identifying pathways and transcription factors that are activated under oxygen concentrations mimicking normal brain tissue microenvironment. To identify the molecular mechanisms mediating the effect of low oxygen levels on NSC biology, we profiled the global effect of sustained, physiologic hypoxia on NSC gene expression using an unbiased approach by genome-wide microarray analysis. NSC were isolated from E13.5 mouse embryos (OF-1 strain) as previously described (Johe et al., 1996). After isolation, cells were immediately cultured at 37°C, 5% CO2 and either 5% or atmospheric (≈21%) oxygen and maintained in these conditions for 2-3 passages (minimum of 10 days). Then, total RNA was extracted, labeled and hybridized in a SurePrint G3 Mouse GE 8x60k array (Agilent Technologies). Four independent experiments were performed using different mouse donors for each experiment.

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