iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer

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 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 and Florent Ginhoux ()
Additional contact information
Dong Shin Park: Technology and Research
Tatsuya Kozaki: Technology and Research
Satish Kumar Tiwari: Technology and Research
Marco Moreira: INSERM U1015, Gustave Roussy Cancer Campus
Ahad Khalilnezhad: Technology and Research
Federico Torta: National University of Singapore
Nicolas Olivié: Institut de Biologie de l’Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University
Chung Hwee Thiam: National University of Singapore
Oniko Liani: Technology and Research
Aymeric Silvin: Technology and Research
Wint Wint Phoo: Agency for Science, Technology and Research
Liang Gao: National University of Singapore
Alexander Triebl: National University of Singapore
Wai Kin Tham: National University of Singapore
Leticia Gonçalves: INSERM U1015, Gustave Roussy Cancer Campus
Wan Ting Kong: Technology and Research
Sethi Raman: Technology and Research
Xiao Meng Zhang: Technology and Research
Garett Dunsmore: INSERM U1015, Gustave Roussy Cancer Campus
Charles Antoine Dutertre: Technology and Research
Salanne Lee: Technology and Research
Jia Min Ong: Technology and Research
Akhila Balachander: Technology and Research
Shabnam Khalilnezhad: Technology and Research
Josephine Lum: Technology and Research
Kaibo Duan: Technology and Research
Ze Ming Lim: Technology and Research
Leonard Tan: Technology and Research
Ivy Low: Technology and Research
Kagistia Hana Utami: Technology and Research
Xin Yi Yeo: Technology and Research
Sylvaine Tommaso: Oncoprot Platform, TBM-Core US 005
Jean-William Dupuy: University of Bordeaux
Balazs Varga: University of Cambridge
Ragnhildur Thora Karadottir: University of Cambridge
Mufeeda Changaramvally Madathummal: Research Support Centre, Agency for Science, Technology and Research (A*STAR)
Isabelle Bonne: National University of Singapore
Benoit Malleret: Technology and Research
Zainab Yasin Binte: Technology and Research
Ngan Wei Da: Technology and Research
Yingrou Tan: Technology and Research
Wei Jie Wong: Shanghai Jiao Tong University School of Medicine
Jinqiu Zhang: Technology and Research
Jinmiao Chen: Technology and Research
Radoslaw M. Sobota: Agency for Science, Technology and Research
Shanshan W. Howland: Technology and Research
Lai Guan Ng: Technology and Research
Frédéric Saltel: Oncoprot Platform, TBM-Core US 005
David Castel: Université Paris-Saclay
Jacques Grill: Université Paris-Saclay
Veronique Minard: INSERM U1015, Gustave Roussy Cancer Campus
Salvatore Albani: SingHealth Duke-NUS Academic Medical Centre
Jerry K. Y. Chan: KK Women’s and Children’s Hospital
Morgane Sonia Thion: Institut de Biologie de l’Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University
Sang Yong Jung: Technology and Research
Markus R. Wenk: National University of Singapore
Mahmoud A. Pouladi: Technology and Research
Claudia Pasqualini: INSERM U1015, Gustave Roussy Cancer Campus
Veronique Angeli: National University of Singapore
Olivier N. F. Cexus: National University of Singapore
Florent Ginhoux: Technology and Research

Nature, 2023, vol. 623, issue 7986, 397-405

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41586-023-06713-1

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