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Axial Elongation of Caudalized Human Pluripotent Stem Cell Organoids Mimics Neural Tube Development

A. R. G. Libby, D. A. Joy, N. H. Elder, E. A. Bulger, M. Z. Krakora, E. A. Gaylord, F. Mendoza-Camacho, T. C. McDevitt
doi: https://doi.org/10.1101/2020.03.05.979732
A. R. G. Libby
1Developmental and Stem Cell Biology PhD Program, University of California, San Francisco, CA
2Gladstone Institutes, San Francisco, CA
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D. A. Joy
2Gladstone Institutes, San Francisco, CA
3UC Berkeley-UC San Francisco Graduate Program in Bioengineering, San Francisco, CA
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N. H. Elder
1Developmental and Stem Cell Biology PhD Program, University of California, San Francisco, CA
2Gladstone Institutes, San Francisco, CA
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E. A. Bulger
1Developmental and Stem Cell Biology PhD Program, University of California, San Francisco, CA
2Gladstone Institutes, San Francisco, CA
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M. Z. Krakora
2Gladstone Institutes, San Francisco, CA
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E. A. Gaylord
1Developmental and Stem Cell Biology PhD Program, University of California, San Francisco, CA
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F. Mendoza-Camacho
2Gladstone Institutes, San Francisco, CA
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T. C. McDevitt
2Gladstone Institutes, San Francisco, CA
4Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA
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  • For correspondence: todd.mcdevitt@gladstone.ucsf.edu
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Abstract

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 induced pluripotent stem cell (hiPSC) aggregates that recapitulates morphologic and gene expression patterns of neural tube development. Axial 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. Finally, CRISPR interference-mediated silencing of BMP inhibitors induced elongation phenotypes that mimicked murine knockout models. These results indicate the potent morphogenic capacity of hiPSC organoids to undergo significant axial elongation in a manner that mimics early human nervous system development.

One sentence summary Here, the authors introduce an organoid model for neural tube development that demonstrates robust Wnt-dependent axial elongation, epithelial compartmentalization, establishment of neural and mesodermal progenitor populations, and morphogenic responsiveness to changes in BMP signaling.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted March 06, 2020.
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Axial Elongation of Caudalized Human Pluripotent Stem Cell Organoids Mimics Neural Tube Development
A. R. G. Libby, D. A. Joy, N. H. Elder, E. A. Bulger, M. Z. Krakora, E. A. Gaylord, F. Mendoza-Camacho, T. C. McDevitt
bioRxiv 2020.03.05.979732; doi: https://doi.org/10.1101/2020.03.05.979732
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Axial Elongation of Caudalized Human Pluripotent Stem Cell Organoids Mimics Neural Tube Development
A. R. G. Libby, D. A. Joy, N. H. Elder, E. A. Bulger, M. Z. Krakora, E. A. Gaylord, F. Mendoza-Camacho, T. C. McDevitt
bioRxiv 2020.03.05.979732; doi: https://doi.org/10.1101/2020.03.05.979732

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