Yu Diankun, Jain Samhita, Wangzhou Andi, Zhu Beika, Shao Wenyuan, Coley-O'Rourke Elena J, De Florencio Stacy, Kim JaeYeon, Choi Jennifer Ja-Yoon, Paredes Mercedes F, Nowakowski Tomasz J, Huang Eric J, Piao Xianhua
Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
Division of Neonatology, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
Nature. 2025 Aug 6. doi: 10.1038/s41586-025-09362-8.
GABAergic neurons are essential cellular components of neural circuits. Their abundance and diversity have increased significantly in the human brain, contributing to the expanded cognitive capacity of humans. However, the developmental mechanism underlying the extended production of GABAergic neurons in the human brain remains elusive. Here we uncovered the microglial regulation of the sustained proliferation of GABAergic progenitors and neuroblasts in the human medial ganglionic eminence (hMGE). We showed that microglia are preferentially distributed in the proliferating zone and identified insulin-like growth factor 1 (IGF1) and its receptor IGR1R as the predicted top ligand-receptor pair underlying microglia-progenitor communication in the prenatal hMGE. Using our newly developed neuroimmune hMGE organoids, which mimic the hMGE cytoarchitecture and developmental trajectory, we demonstrated that microglia-derived IGF1 promotes progenitor proliferation and production of GABAergic neurons. Conversely, IGF1-neutralizing antibodies and IGF1 knockout human embryonic stem-cell-induced microglia abolish the induced microglia-mediated progenitor proliferation. Together, these findings revealed a previously unappreciated role of microglia-derived IGF1 in promoting the proliferation of neural progenitors and the development of GABAergic neurons in the human brain.
γ-氨基丁酸能神经元是神经回路的重要细胞组成部分。它们在人类大脑中的数量和多样性显著增加，这有助于人类认知能力的扩展。然而，人类大脑中γ-氨基丁酸能神经元产生增加的发育机制仍不清楚。在这里，我们揭示了小胶质细胞对人类内侧神经节隆起（hMGE）中γ-氨基丁酸能祖细胞和成神经细胞持续增殖的调节作用。我们发现小胶质细胞优先分布在增殖区，并确定胰岛素样生长因子1（IGF1）及其受体IGR1R是产前hMGE中小胶质细胞与祖细胞通讯的预测顶级配体-受体对。使用我们新开发的模拟hMGE细胞结构和发育轨迹的神经免疫hMGE类器官，我们证明小胶质细胞衍生的IGF1促进祖细胞增殖和γ-氨基丁酸能神经元的产生。相反，IGF1中和抗体和IGF1基因敲除的人类胚胎干细胞诱导的小胶质细胞消除了诱导的小胶质细胞介导的祖细胞增殖。总之，这些发现揭示了小胶质细胞衍生的IGF1在促进人类大脑中神经祖细胞增殖和γ-氨基丁酸能神经元发育方面以前未被认识到的作用。
