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Axial Elongation of Caudalized Human Pluripotent Stem Cell Organoids Mimics Neural Tube Development [RNA-Seq]

ABSTRACT: Axial Elongation of Caudalized Human Pluripotent Stem Cell Organoids Mimics Neural Tube Development [RNA-Seq]

PROVIDER: PRJNA649553 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12344700_1.fastq.gz	Fastqsanger.gz
	SRR12344700_2.fastq.gz	Fastqsanger.gz
	SRR12344701_1.fastq.gz	Fastqsanger.gz
	SRR12344701_2.fastq.gz	Fastqsanger.gz
	SRR12344702_1.fastq.gz	Fastqsanger.gz

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Axial Elongation of Caudalized Human Pluripotent Stem Cell Organoids Mimics Neural Tube Development [RNA-Seq]

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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Axial Elongation of Caudalized Human Pluripotent Stem Cell Organoids Mimics Neural Tube Development [scRNA-Seq]

Project description:Axial Elongation of Caudalized Human Pluripotent Stem Cell Organoids Mimics Neural Tube Development [scRNA-Seq]

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Controlling organoid symmetry breaking uncovers an excitable system underlying human axial elongation

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.

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Project description:Axial elongation of the neural tube is crucial during mammalian embryogenesis for anterior-posterior body axis establishment and subsequent spinal cord development, but these processes cannot be interrogated directly in humans as they occur post-implantation. Here, we report an organoid model of neural tube extension derived from human pluripotent stem cell (hPSC) aggregates that have been caudalized with Wnt agonism, enabling them to recapitulate aspects of the morphological and temporal gene expression patterns of neural tube development. Elongating organoids consist largely of neuroepithelial compartments and contain TBXT+SOX2+ neuro-mesodermal progenitors in addition to PAX6+NES+ neural progenitors. A critical threshold of Wnt agonism stimulated singular axial extensions while maintaining multiple cell lineages, such that organoids displayed regionalized anterior-to-posterior HOX gene expression with hindbrain (HOXB1) regions spatially distinct from brachial (HOXC6) and thoracic (HOXB9) regions. CRISPR interference-mediated silencing of TBXT, a Wnt pathway target, increased neuroepithelial compartmentalization, abrogated HOX expression and disrupted uniaxial elongation. Together, these results demonstrate the potent capacity of caudalized 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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Axial Elongation of Caudalized Human Pluripotent Stem Cell Organoids Mimics Neural Tube Development

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Project description:Axial development of mammals is a dynamic process involving several coordinated morphogenetic events, including axial elongation, somitogenesis, and neural tube formation. To gain insight into the signals control the dynamics of human axial morphogenesis, we generated hundreds of axially elongating organoids by inducing anteroposterior symmetry breaking of spatially coupled epithelial cysts derived from human pluripotent stem cells. Each organoid was composed of a neural tube flanked by presomitic mesoderm sequentially segmented into somites. Periodic activation of the somite differentiation gene MESP2 coincided in space and time with anteriorly traveling segmentation clock waves in the presomitic mesoderm of the organoids, recapitulating critical aspects of somitogenesis. Through timed perturbations of organoids, we demonstrated that FGF and WNT signaling play distinct roles in axial elongation and somitogenesis and that FGF signaling gradients drive the segmentation clock waves. By generating and perturbing organoids that robustly recapitulate the architecture and dynamics of multiple axial tissues in human embryos, this work offers a means to dissect complex mechanisms underlying human embryogenesis.

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