Actuation Enhances Patterning in Human Neural Tube Organoids
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ABSTRACT:
PROVIDER: PRJNA645161 | ENA |
REPOSITORIES: ENA
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Project description:Tissues achieve their complex spatial organization though physical interactions mediated by mechanical forces. Current strategies to generate in-vitro tissues have largely failed to implement such active, dynamically coordinated mechanical manipulations, relying instead on extracellular matrices which respond to, rather than impose mechanical forces. Here we develop devices which enable the actuation of organoids, and show that active mechanical forces increase growth and lead to enhanced patterning in an organoid model of the neural tube derived from single human pluripotent stem cells (hPSC). We demonstrate that organoid mechanoregulation due to actuation operates in a temporally restricted competence window, and that organoid response to stretch is mediated extracellularly by matrix stiffness and intracellularly by cytoskeleton contractility and planar cell polarity. Exerting active mechanical forces on organoids using the approaches developed here is widely applicable and should enable the generation of more reproducible, programmable organoid shape, identity and patterns, opening avenues for use of these tools in regenerative medicine and disease modelling applications.
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Project description:Self-elongating neural tube organoids recapitulate key aspects of the morphology, anterior-posterior patterning, neural crest emergence and neural differentiation of mouse embryo in vivo by self-organization. We used single-cell RNA sequencing (scRNA-seq) to analyse the cell types and to reveal the sequence of transcriptional events in the emergence of neural crest cells and neural differentiation.
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Project description:During mammalian embryogenesis, axial elongation of the neural tube is critical for establishing the anterior-posterior body axis, but is difficult to interrogate directly because it occurs post-implantation. Here we report an organoid model of neural tube extension using human pluripotent stem cell (hPSC) aggregates that recapitulates the morphologic and temporal gene expression patterns of neural tube development. Axially extending organoids consisted of longitudinally elongated epithelial compartments and contained TBXT(+)SOX2(+) neuromesodermal progenitors, PAX6(+) Nestin(+) neural progenitor populations, and MEOX1(+) paraxial mesoderm populations. Wnt agonism stimulated axial extensions in a dose-dependent manner and elongated organoids displayed regionalized rostral-caudal HOX gene expression, with hindbrain (HOXB1) expression distinct from brachial (HOXC6) and thoracic (HOXB9) expression. CRISPR interference-mediated silencing of BMP inhibitors induced elongation phenotypes that mimicked murine knockout models, and knock-down of the downstream Wnt target, TBXT, increased neuroepithelial compartmentalization and resulted in multiple extensions. These results indicate the potent morphogenic capacity of hPSC organoids to undergo axial elongation in a manner that can be used to dissect the cellular organization and patterning decisions that dictate early human nervous system development.
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Project description:During mammalian embryogenesis, axial elongation of the neural tube is critical for establishing the anterior-posterior body axis, but is difficult to interrogate directly because it occurs post-implantation. Here we report an organoid model of neural tube extension using human pluripotent stem cell (hPSC) aggregates that recapitulates the morphologic and temporal gene expression patterns of neural tube development. Axially extending organoids consisted of longitudinally elongated epithelial compartments and contained TBXT(+)SOX2(+) neuromesodermal progenitors, PAX6(+) Nestin(+) neural progenitor populations, and MEOX1(+) paraxial mesoderm populations. Wnt agonism stimulated axial extensions in a dose-dependent manner and elongated organoids displayed regionalized rostral-caudal HOX gene expression, with hindbrain (HOXB1) expression distinct from brachial (HOXC6) and thoracic (HOXB9) expression. CRISPR interference-mediated silencing of BMP inhibitors induced elongation phenotypes that mimicked murine knockout models, and knock-down of the downstream Wnt target, TBXT, increased neuroepithelial compartmentalization and resulted in multiple extensions. These results indicate the potent morphogenic capacity of hPSC organoids to undergo axial elongation in a manner that can be used to dissect the cellular organization and patterning decisions that dictate early human nervous system development.
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Project description:We describe the transcriptomic differences in FoxA2-Venus high and low cell populations in neural tube organoids.
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Project description:We analyzed scRNA-seq data in human pluripotent stem cells derived neural tube models. This in vitro system recapitulates some key aspects of neural patterning in the entire neural tube, including both brain and SC regions, along both rostral-caudal and dorsal-ventral axes
2022-01-28 | GSE194225 | GEO
Project description:The neural tube (NT) has been a hallmark example of embryonic induction and patterning whereby the notochord induces an organiser, the floorplate, that secretes Sonic Hedgehog (SHH) to pattern the surrounding field of neural progenitors. On the other hand, NT organoids (NTOs) formed from embryonic stem cells (ESCs) undergo spontaneous floorplate formation and patterning in the absence of their normal embryonic inducers. Understanding how stem cells undergo regulative organiser formation is a central challenge in biology. Here, we investigated the self-organisation of a SHH-expressing floorplate organiser using clonal mouse NTOs. Expression of FOXA2, a floorplate transcription factor, was initially spatially scattered before resolving into multiple clusters. These FOXA2+ clusters underwent competition and physical sorting, resulting in a stable “winning” floorplate. We identified BMP signalling as a key governor of long-range cluster competition. FOXA2+ clusters expressed BMP4 ligand suppressing FOXA2 in receiving cells, while simultaneously expressing the BMP-inhibitor NOGGIN to secure FOXA2+ cluster survival. Genetic mutation of Noggin perturbed the floorplate not only in NTOs but also in vivo at the mid-hindbrain region of the mouse NT. These results demonstrate how the floorplate can form autonomously without its well-known inducer, the notochord, suggesting redundant mechanisms ensuring robustness. Defining molecular pathways that govern organiser self-organisation is critical in harnessing the developmental plasticity of stem cells toward directed tissue engineering.
2024-04-23 | GSE260579 | GEO
Project description:The goal of this study was to test the hypothesis that BMP signaling regulates patterning of human CDX2+ gut tube cultures (Spence et al 2011, Watson et al. 2014). The study is comprised of 2 separate experiments. The first experiment was to determine the immediate impact of BMP signaling on CDX2+ gut tube cultures. To do so we tested spheroids, spheroids after plating in Matrigel and exposed to 3 days of Noggin (100ng/mL), spheroids after plating in Matrigel and exposed to 3 days of EGF alone (100ng/mL, Control), and spheroids after plating in Matrigel and exposed to 3 days of BMP2 (100ng/mL). RNA was collected from spheroids and spheroids after 3 days of patterning. The second experiment examined if patterning was maintained after this initial 3 days of patterning and an addition 8-10 weeks following transplantation in vivo. To do this we grew all Matrigel plated spheroids for an additional 25 days in media containing EGF alone (Control media). We then transplanted these organoids under the mouse kidney capsule and allowed them to mature for 8-10 weeks. We then collected RNA from the transplanted organoids.
2017-04-20 | E-MTAB-5658 | biostudies-arrayexpress