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.
