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Title: iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer
Authors: Park, Dong Shin
Kozaki, Tatsuya
Tiwari, Satish Kumar
Moreira, Marco
Khalilnezhad, Ahad
Torta, Federico 
Olivie, Nicolas
Thiam, Chung Hwee 
Liani, Oniko
Silvin, Aymeric
Phoo, Wint Wint 
Gao, Liang 
Triebl, Alexander 
Tham, Wai Kin 
Goncalves, Leticia
Kong, Wan Ting
Raman, Sethi
Zhang, Xiao Meng
Dunsmore, Garett
Dutertre, Charles Antoine
Lee, Salanne
Ong, Jia Min
Balachander, Akhila
Khalilnezhad, Shabnam
Lum, Josephine
Duan, Kaibo
Lim, Ze Ming
Tan, Leonard
Low, Ivy
Utami, Kagistia Hana
Yeo, Xin Yi
Di Tommaso, Sylvaine
Dupuy, Jean-William
Varga, Balazs
Karadottir, Ragnhildur Thora
Madathummal, Mufeeda Changaramvally
Bonne, Isabelle 
Malleret, Benoit 
Binte, Zainab Yasin
Da, Ngan Wei
Tan, Yingrou
Wong, Wei Jie
Zhang, Jinqiu
Chen, Jinmiao
Sobota, Radoslaw M
Howland, Shanshan W
Ng, Lai Guan 
Saltel, Frederic
Castel, David
Grill, Jacques
Minard, Veronique
Albani, Salvatore 
Chan, Jerry KY 
Thion, Morgane Sonia
Jung, Sang Yong
Wenk, Markus R 
Pouladi, Mahmoud A
Pasqualini, Claudia
Angeli, Veronique 
Cexus, Olivier NF 
Ginhoux, Florent 
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
Issue Date: 9-Nov-2023
Citation: Park, Dong Shin, Kozaki, Tatsuya, Tiwari, Satish Kumar, Moreira, Marco, Khalilnezhad, Ahad, Torta, Federico, Olivie, Nicolas, Thiam, Chung Hwee, Liani, Oniko, Silvin, Aymeric, Phoo, Wint Wint, Gao, Liang, Triebl, Alexander, Tham, Wai Kin, Goncalves, Leticia, Kong, Wan Ting, Raman, Sethi, Zhang, Xiao Meng, Dunsmore, Garett, Dutertre, Charles Antoine, Lee, Salanne, Ong, Jia Min, Balachander, Akhila, Khalilnezhad, Shabnam, Lum, Josephine, Duan, Kaibo, Lim, Ze Ming, Tan, Leonard, Low, Ivy, Utami, Kagistia Hana, Yeo, Xin Yi, Di Tommaso, Sylvaine, Dupuy, Jean-William, Varga, Balazs, Karadottir, Ragnhildur Thora, Madathummal, Mufeeda Changaramvally, Bonne, Isabelle, Malleret, Benoit, Binte, Zainab Yasin, Da, Ngan Wei, Tan, Yingrou, Wong, Wei Jie, Zhang, Jinqiu, Chen, Jinmiao, Sobota, Radoslaw M, Howland, Shanshan W, Ng, Lai Guan, Saltel, Frederic, Castel, David, Grill, Jacques, Minard, Veronique, Albani, Salvatore, Chan, Jerry KY, Thion, Morgane Sonia, Jung, Sang Yong, Wenk, Markus R, Pouladi, Mahmoud A, Pasqualini, Claudia, Angeli, Veronique, Cexus, Olivier NF, Ginhoux, Florent (2023-11-09). iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer. NATURE 623 (7986). ScholarBank@NUS Repository.
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.
Source Title: NATURE
ISSN: 1476-4687
DOI: 10.1038/s41586-023-06713-1
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