2025-05-01 イェール大学
<関連情報>
- https://news.yale.edu/2025/05/01/how-molecular-traffic-cops-guide-development-human-brain
- https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00141-9
WNTとSHHの直交勾配を持つオルガノイドを用いたヒトの脳領域の特定により、細胞株によるパターン形成の差異が明らかになった Specification of human brain regions with orthogonal gradients of WNT and SHH in organoids reveals patterning variations across cell lines
Soraya Scuderi ∙ Tae-Yun Kang ∙ Alexandre Jourdon ∙ … ∙ Alexej Abyzov, ∙ Andre Levchenko ∙ Flora M. Vaccarino
Cell Stem Cell Published:May 1, 2025
DOI:https://doi.org/10.1016/j.stem.2025.04.006
Graphical abstract
Highlights
- Orthogonal WNTs/SHH gradients pattern organoids into forebrain, midbrain, and hindbrain
- WNT/SHH crosstalk triggers transcriptional programs driving lineage specification
- There are donor- and line-specific variations in morphogen response
- Patterned regions generate neuronal networks with different functional organization
Summary
The repertoire of neurons and their progenitors depends on their location along the antero-posterior and dorso-ventral axes of the neural tube. To model these axes, we designed the Dual Orthogonal-Morphogen Assisted Patterning System (Duo-MAPS) diffusion device to expose spheres of induced pluripotent stem cells (iPSCs) to concomitant orthogonal gradients of a posteriorizing and a ventralizing morphogen, activating WNT and SHH signaling, respectively. Comparison with single-cell transcriptomes from the fetal human brain revealed that Duo-MAPS-patterned organoids generated an extensive diversity of neuronal lineages from the forebrain, midbrain, and hindbrain. WNT and SHH crosstalk translated into early patterns of gene expression programs associated with the generation of specific brain lineages with distinct functional networks. Human iPSC lines showed substantial interindividual and line-to-line variations in their response to morphogens, highlighting that genetic and epigenetic variations may influence regional specification. Morphogen gradients promise to be a key approach to model the brain in its entirety.
