Gastruloids generated without exogenous Wnt activation develop anterior neural tissues [EmbryoidsTruseq2]
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PROVIDER: PRJNA718749 | ENA |
REPOSITORIES: ENA
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Project description:Here we describe an approach to generate gastruloids that have a more complete antero-posterior development. We used bioengineered hydrogel microwell arrays to promote the robust derivation of mouse ESCs into post-implantation epiblast-like (EPI) aggregates in a reproducible and scalable manner. These EPI aggregates break symmetry and axially elongate without external chemical stimulation. Inhibition of WNT signaling in early stages of development leads to the formation of gastruloids with anterior neural tissues.
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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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Project description:Primordial Germ Cells (PGCs) are a rare population of cells specified early in embryonic development that give rise to gametes - sperm and egg cells. Current in vitro systems to derive PGC-like cells (PGCLCs) from pluripotent cells use large embryoid bodies, exposed to signalling cocktails, that do not recapitulate the native embryonic environment during PGC formation. Here we show that mouse gastruloids, three-dimensional in vitro models of gastrulation, generate a population of Gastruloid-derived PGC-like cells (Gld-PGCLCs) that resemble early PGCs in vivo. Importantly, the conserved organisation of mouse gastruloids leads to coordinated spatial and temporal localisation of Gld-PGCLCs relative to surrounding somatic cells, even in the absence of exogenous PGC-specific signalling or extraembryonic tissues. In gastruloids, self-organised interactions between cells and tissues, including the endodermal epithelium, enables the specification, migration, and subsequent maturation of a pool of Gld-PGCLCs. As such, mouse gastruloids represent a new source of PGCLCs in vitro and, due to their inherent co-development, serve as a novel model of dynamic PGC development within integrated tissue environments.
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Project description:Organoids are powerful models for studying tissue development, physiology, and disease. However, current culture systems disrupt the inductive tissue-tissue interactions needed for the complex morphogenetic processes of native organogenesis. Here we show that mouse embryonic stem cells (mESCs) can be coaxed to robustly undergo fundamental steps of early heart organogenesis with an in vivo-like spatiotemporal fidelity. These axially patterned embryonic organoids (gastruloids) mimic embryonic development, and support the generation of cardiovascular progenitors, including first and second heart fields. The cardiac progenitors self-organize into an anterior domain reminiscent of a cardiac crescent before forming a beating cardiac tissue near a putative primitive gut-like tube, from which it is separated by an endocardial-like layer. These findings unveil the surprising morphogenetic potential of mESCs to execute key aspects of organogenesis through the coordinated development of multiple tissues. This platform could be an excellent tool for studying heart development in unprecedented detail and throughput. For data exploration, execute in R-Studio Explore_Data.R in https://github.com/nbroguiere/Cardiac_Gastruloids
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