Li Jia, Liu Ming-Jian, Du Wen-Jie, Peng Xiao-Lan, Deng Hao, Zi Hua-Xing, Shang Han-Bing, Du Jiu-Lin
Institute of Neuroscience, Key Laboratory of Brain Cognition and Brain-Inspired Intelligence Technology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
Cell. 2025 Jun 12;188(12):3274-3290.e16. doi: 10.1016/j.cell.2025.04.008. Epub 2025 Apr 30.
The nervous system regulates peripheral immune responses under physiological and pathological conditions, but the brain's impact on immune system development remains unknown. Meningeal mural lymphatic endothelial cells (muLECs), embedded in the leptomeninges, form an immune niche surrounding the brain that contributes to brain immunosurveillance. Here, we report that the brain controls the development of muLECs via a specialized glial subpopulation, slc6a11b+ radial astrocytes (RAs), a process modulated by neural activity in zebrafish. slc6a11b+ RAs, with processes extending to the meninges, govern muLEC formation by expressing vascular endothelial growth factor C (vegfc). Moreover, neural activity regulates muLEC development, and this regulation requires Vegfc in slc6a11b+ RAs. Intriguingly, slc6a11b+ RAs cooperate with calcium-binding EGF domain 1 (ccbe1)+ fibroblasts to restrict muLEC growth on the brain surface via controlling mature Vegfc distribution. Thus, our study uncovers a glia-mediated and neural-activity-regulated control of brain lymphatic development and highlights the importance of inter-tissue cellular cooperation in development.
神经系统在生理和病理条件下调节外周免疫反应，但大脑对免疫系统发育的影响尚不清楚。嵌入软脑膜的脑膜壁层淋巴管内皮细胞（muLEC）形成了围绕大脑的免疫微环境，有助于大脑的免疫监视。在这里，我们报告大脑通过一种特殊的胶质亚群，即slc6a11b+放射状星形胶质细胞（RA）来控制muLEC的发育，这一过程在斑马鱼中受神经活动调节。slc6a11b+ RA的突起延伸至脑膜，通过表达血管内皮生长因子C（vegfc）来控制muLEC的形成。此外，神经活动调节muLEC的发育，而这种调节需要slc6a11b+ RA中的Vegfc。有趣的是，slc6a11b+ RA与钙结合EGF结构域1（ccbe1）+成纤维细胞合作，通过控制成熟Vegfc的分布来限制muLEC在脑表面的生长。因此，我们的研究揭示了一种由胶质细胞介导且受神经活动调节的大脑淋巴管发育控制机制，并强调了组织间细胞合作在发育中的重要性。
