iPS 细胞衍生的小胶质细胞通过胆固醇转移促进大脑类器官成熟。
iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer.
发表日期：2023 Nov 01
作者：
Dong Shin Park, Tatsuya Kozaki, Satish Kumar Tiwari, Marco Moreira, Ahad Khalilnezhad, Federico Torta, Nicolas Olivié, Chung Hwee Thiam, Oniko Liani, Aymeric Silvin, Wint Wint Phoo, Liang Gao, Alexander Triebl, Wai Kin Tham, Leticia Gonçalves, Wan Ting Kong, Sethi Raman, Xiao Meng Zhang, Garett Dunsmore, Charles Antoine Dutertre, Salanne Lee, Jia Min Ong, Akhila Balachander, Shabnam Khalilnezhad, Josephine Lum, Kaibo Duan, Ze Ming Lim, Leonard Tan, Ivy Low, Kagistia Hana Utami, Xin Yi Yeo, Sylvaine Di Tommaso, Jean-William Dupuy, Balazs Varga, Ragnhildur Thora Karadottir, Mufeeda Changaramvally Madathummal, Isabelle Bonne, Benoit Malleret, Zainab Yasin Binte, Ngan Wei Da, Yingrou Tan, Wei Jie Wong, Jinqiu Zhang, Jinmiao Chen, Radoslaw M Sobota, Shanshan W Howland, Lai Guan Ng, Frédéric Saltel, David Castel, Jacques Grill, Veronique Minard, Salvatore Albani, Jerry K Y Chan, Morgane Sonia Thion, Sang Yong Jung, Markus R Wenk, Mahmoud A Pouladi, Claudia Pasqualini, Veronique Angeli, Olivier N F Cexus, Florent Ginhoux
来源：
Stem Cell Research & Therapy
摘要：
小胶质细胞是一种专门的大脑驻留巨噬细胞，由定植于胚胎大脑的原始巨噬细胞产生。小胶质细胞对大脑发育的多个方面都有贡献，但由于相关组织的接触有限，它们在早期人类大脑中的确切作用仍然知之甚少2-6。由人类诱导多能干细胞产生的大脑类器官概括了人类胚胎大脑发育的一些关键特征7-10。然而，目前的方法没有纳入小胶质细胞或解决它们在类器官成熟中的作用11-21。在这里，我们通过将大脑类器官与由相同的人类诱导多能干细胞 (iMac)22 产生的原始巨噬细胞共培养，生成了足够小胶质细胞的大脑类器官。在类器官共培养中，iMac 分化为具有小胶质细胞样表型和功能的细胞 (iMicro)，并调节神经元祖细胞 (NPC) 分化，限制 NPC 增殖并促进轴突发生。从机制上讲，iMicro 含有高水平的 PLIN2 脂滴，可输出胆固醇及其酯，这些胆固醇及其酯被类器官中的 NPC 吸收。我们还在小鼠和人类胚胎大脑中检测到负载 PLIN2 脂滴的小胶质细胞。总体而言，我们的方法通过整合小胶质细胞，极大地推进了当前的人脑类器官方法，正如发现小胶质细胞和 NPC 之间脂质介导的串扰的关键途径所说明的那样，该途径可改善神经发生。© 2023。作者，下施普林格自然有限公司的独家许可。
Microglia are specialized brain-resident macrophages that arise from primitive macrophages colonizing the embryonic brain1. Microglia contribute to multiple aspects of brain development, but their precise roles in the early human brain remain poorly understood owing to limited access to relevant tissues2-6. The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development7-10. However, current approaches do not incorporate microglia or address their role in organoid maturation11-21. Here we generated microglia-sufficient brain organoids by coculturing brain organoids with primitive-like macrophages generated from the same human induced pluripotent stem cells (iMac)22. In organoid cocultures, iMac differentiated into cells with microglia-like phenotypes and functions (iMicro) and modulated neuronal progenitor cell (NPC) differentiation, limiting NPC proliferation and promoting axonogenesis. Mechanistically, iMicro contained high levels of PLIN2+ lipid droplets that exported cholesterol and its esters, which were taken up by NPCs in the organoids. We also detected PLIN2+ lipid droplet-loaded microglia in mouse and human embryonic brains. Overall, our approach substantially advances current human brain organoid approaches by incorporating microglial cells, as illustrated by the discovery of a key pathway of lipid-mediated crosstalk between microglia and NPCs that leads to improved neurogenesis.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.