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Specification of human brain regions with orthogonal gradients of WNT and SHH in organoids reveals patterning variations across cell lines

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Cell Stem Cell 2025年第6期32卷 970-989.e11页

作者： Scuderi, Soraya Kang, Tae-Yun Jourdon, Alexandre Nelson, Alex Yang, Liang Wu, Feinan Anderson, George M. Mariani, Jessica Tomasini, Livia Sarangi, Vivekananda Abyzov, Alexej Levchenko, Andre Vaccarino, Flora M. Program in Neurodevelopment and Regeneration Yale University New Haven 06520 CT United States Child Study Center Yale University New Haven 06520 CT United States Systems Biology Institute Yale University West Haven 06516 CT United States Department of Biomedical Engineering Yale University New Haven 06520 CT United States Department of Health Sciences Research Mayo Clinic Rochester 55905 MN United States Department of Neuroscience Yale University New Haven 06520 CT United States Yale Stem Cell Center Yale University New Haven 06520 CT United States

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. © 2025 Elsevier Inc.

关键词： brain development gradients human iPSC morphogens organoids patterning SHH WNT

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