Varela Maria C, Walker Miranda P, Bok Jeyoon, Crespo Emmanuel L, Thenstedt Tyler, Goldstein Leah, Tidball Andrew M, Li Jun Z, Yuan Yukun, Isom Lori L, Fu Jianping, Uhler Michael, Parent Jack M
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA.
Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI, USA.
bioRxiv. 2025 Jul 4:2025.07.01.662594. doi: 10.1101/2025.07.01.662594.
The medial ganglionic eminence (MGE) gives rise to parvalbumin (PV)- and somatostatin (SST)-expressing cortical interneurons essential for regulating cortical excitability. Although PV interneurons are linked to various neurodevelopmental and neurodegenerative disorders, reliably generating them from human pluripotent stem cells (hPSCs) has been extremely challenging. We present a robust, reproducible protocol for generating single-rosette MGE organoids (MGEOs) from hPSCs. Transcriptomic analyses reveal that MGEOs exhibit MGE regional identity and faithfully model the developing human fetal MGE. As MGEOs mature, they generate abundant PV-expressing cortical interneurons, including putative basket and axoaxonic cells, at a scale not previously achieved . When fused with hPSC-derived cortical organoids, these interneurons rapidly migrate into cortical regions, integrate into excitatory networks, and contribute to complex electrophysiological patterns and the emergence of large numbers of fast-spiking neurons. MGEOs thus offer a powerful approach for probing human MGE-lineage cortical and subcortical GABAergic neuron development, modeling various neuropsychiatric disorders, and advancing cell-based therapies for neurodevelopmental and neurodegenerative disorders.
内侧神经节隆起（MGE）产生表达小白蛋白（PV）和生长抑素（SST）的皮质中间神经元，这些神经元对于调节皮质兴奋性至关重要。尽管PV中间神经元与多种神经发育和神经退行性疾病有关，但从人多能干细胞（hPSC）中可靠地生成它们一直极具挑战性。我们提出了一种从hPSC生成单玫瑰花结MGE类器官（MGEO）的稳健、可重复方案。转录组分析表明，MGEO表现出MGE区域特征，并忠实地模拟发育中的人类胎儿MGE。随着MGEO成熟，它们会产生大量表达PV的皮质中间神经元，包括假定的篮状细胞和轴-轴突细胞，其规模是以前未曾达到的。当与hPSC衍生的皮质类器官融合时，这些中间神经元会迅速迁移到皮质区域，整合到兴奋性网络中，并促成复杂的电生理模式以及大量快速放电神经元的出现。因此，MGEO为探究人类MGE谱系的皮质和皮质下GABA能神经元发育、模拟各种神经精神疾病以及推进针对神经发育和神经退行性疾病的细胞疗法提供了一种强大的方法。
