Axial elongation of caudalized human organoids mimics aspects of neural tube development.

Autor:	Libby ARG; Developmental and Stem Cell Biology PhD Program, University of California, San Francisco, CA 94143, USA.; Gladstone Institutes, San Francisco, CA 94158, USA., Joy DA; Gladstone Institutes, San Francisco, CA 94158, USA.; UC Berkeley-UC San Francisco Graduate Program in Bioengineering, San Francisco, CA 94158, USA., Elder NH; Developmental and Stem Cell Biology PhD Program, University of California, San Francisco, CA 94143, USA.; Gladstone Institutes, San Francisco, CA 94158, USA., Bulger EA; Developmental and Stem Cell Biology PhD Program, University of California, San Francisco, CA 94143, USA.; Gladstone Institutes, San Francisco, CA 94158, USA., Krakora MZ; Gladstone Institutes, San Francisco, CA 94158, USA., Gaylord EA; Developmental and Stem Cell Biology PhD Program, University of California, San Francisco, CA 94143, USA., Mendoza-Camacho F; Developmental and Stem Cell Biology PhD Program, University of California, San Francisco, CA 94143, USA., Butts JC; Gladstone Institutes, San Francisco, CA 94158, USA., McDevitt TC; Gladstone Institutes, San Francisco, CA 94158, USA.; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA.
Jazyk:	angličtina
Zdroj:	Development (Cambridge, England) [Development] 2021 Jun 15; Vol. 148 (12). Date of Electronic Publication: 2021 Jun 18.
DOI:	10.1242/dev.198275
Abstrakt:	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. Competing Interests: Competing interests The authors declare no competing or financial interests. (© 2021. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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