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, CT 06520, USA; Child Study Center, Yale University, New Haven, CT 06520, USA.
Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Systems Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
Cell Stem Cell. 2025 Jun 5;32(6):970-989.e11. doi: 10.1016/j.stem.2025.04.006. Epub 2025 May 1.
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.
神经元及其祖细胞的谱系取决于它们在神经管前后轴和背腹轴上的位置。为了模拟这些轴，我们设计了双正交形态发生素辅助模式系统（Duo-MAPS）扩散装置，以使诱导多能干细胞（iPSC）球暴露于分别激活WNT和SHH信号传导的后化和腹化形态发生素的伴随正交梯度中。与来自胎儿人类大脑的单细胞转录组进行比较发现，Duo-MAPS模式化的类器官产生了来自前脑、中脑和后脑的广泛多样的神经元谱系。WNT和SHH信号的相互作用转化为与具有不同功能网络的特定脑谱系生成相关的早期基因表达程序模式。人类iPSC系在对形态发生素的反应中表现出显著的个体间和系间差异，这突出表明遗传和表观遗传变异可能影响区域特化。形态发生素梯度有望成为一种整体模拟大脑的关键方法。
