HOPX 调控人干细胞来源的外侧放射状胶质样细胞的发育与谱系进程
HOPX regulates the development and lineage progression of human stem cell-derived outer radial glia-like cells
外侧放射状胶质（oRG）细胞在人类胎儿大脑皮层中数量丰富，在啮齿类动物中却很少见，其分子调控机制一直不清楚。HOPX 是公认的 oRG 标志物，但它在人脑皮层发育中的功能此前未被阐明。作者用 CRISPR-Cas9 基因编辑技术在人多能干细胞中敲除 HOPX，发现在二维神经培养和三维皮层类器官中，HOPX 缺失会损害 oRG 样细胞的扩增和谱系进程：前体细胞增殖减少、神经发生减弱，并过早向星形胶质细胞和少突胶质细胞方向分化。类器官外层脑室下区变小、神经元产出减少、胶质发生提前。机制上，HOPX 缺失影响 PI3K-mTOR 信号通路。这项研究把 HOPX 确认为 oRG 样细胞维持及神经-胶质平衡的重要调控因子。
为什么推荐给您：首次阐明 HOPX 在人脑发育中的功能，属重要新机制，但为人干细胞体外研究。
不需要生物学背景，多打比方
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摘要Abstract
Outer radial glia (oRG) are abundant in the human fetal cortex but rare in rodents, yet their molecular regulation remains poorly understood. Although the homeodomain-only protein X (HOPX) is a well-established oRG marker, its functional role in human cortical development remains undefined. Using CRISPR-Cas9 gene editing in human pluripotent stem cells, we show that HOPX loss impairs the expansion and lineage progression of oRG-like cells in two-dimensional neural cultures and three-dimensional cortical organoids. HOPX knockout precursors exhibit reduced proliferation, diminished neurogenesis, and premature differentiation toward astrocytic and oligodendrocytic lineages. HOPX-deficient organoids display reduced outer subventricular zone size, decreased neuronal output, and early gliogenesis. Mechanistically, HOPX loss impairs PI3K-mTOR signaling. Transcriptomic analysis identifies HOPX-regulated programs governing gliogenic competence, mTOR, and Wnt signaling. Together, these findings identify HOPX as an important regulator of oRG-like cell maintenance and the neurogenic-gliogenic balance, providing insight into the molecular programs governing human neural progenitor expansion.