新加坡國立大學(xué)Florent Ginhoux課題組發(fā)現(xiàn)，iPS細(xì)胞衍生的小膠質(zhì)細(xì)胞通過膽固醇轉(zhuǎn)移促進(jìn)大腦類器官成熟。這一研究成果于2023年11月1日在線發(fā)表在國際學(xué)術(shù)期刊《自然》上。
研究人員通過將腦器官組織與由相同的人類誘導(dǎo)多能干細(xì)胞（iMac）生成的類原始巨噬細(xì)胞共培養(yǎng)，生成了小膠質(zhì)細(xì)胞充足的腦器官組織。在類器官共培養(yǎng)中，iMac分化成具有小膠質(zhì)細(xì)胞樣表型和功能的細(xì)胞（iMicro），并調(diào)節(jié)神經(jīng)元祖細(xì)胞（NPC）的分化，限制NPC增殖，促進(jìn)軸突生長。從機(jī)理上講，iMicro含有大量PLIN2+脂滴，這些脂滴輸出膽固醇及其酯類，被器官組織中的NPC吸收。研究人員還在小鼠和人類胚胎大腦中檢測到了含有PLIN2+脂滴的小膠質(zhì)細(xì)胞。
總之，這個(gè)方法通過納入小膠質(zhì)細(xì)胞，大大推進(jìn)了當(dāng)前的人腦類器官方法，這體現(xiàn)在其發(fā)現(xiàn)了小膠質(zhì)細(xì)胞和鼻咽癌細(xì)胞之間脂質(zhì)介導(dǎo)的串聯(lián)關(guān)鍵途徑，從而改善了神經(jīng)發(fā)生。
據(jù)介紹，小膠質(zhì)細(xì)胞是特化的腦駐留巨噬細(xì)胞，由胚胎大腦中定植的原始巨噬細(xì)胞產(chǎn)生。小膠質(zhì)細(xì)胞在大腦發(fā)育的多個(gè)方面做出了貢獻(xiàn)，但由于獲取相關(guān)組織的途徑有限，人們對它們在人類早期大腦中的確切作用仍然知之甚少。由人類誘導(dǎo)多能干細(xì)胞生成的腦組織器官再現(xiàn)了人類胚胎大腦發(fā)育的一些關(guān)鍵特征。然而，目前的方法沒有結(jié)合小膠質(zhì)細(xì)胞，也沒有解決它們在類器官成熟中的作用。
附：英文原文
Title: iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer
Author: Park, Dong Shin, Kozaki, Tatsuya, Tiwari, Satish Kumar, Moreira, Marco, Khalilnezhad, Ahad, Torta, Federico, Olivi, Nicolas, Thiam, Chung Hwee, Liani, Oniko, Silvin, Aymeric, Phoo, Wint Wint, Gao, Liang, Triebl, Alexander, Tham, Wai Kin, Gonalves, 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, Wei Da, Ngan, Tan, Yingrou, Wong, Wei Jie, Zhang, Jinqiu, Chen, Jinmiao, Sobota, Radoslaw M., Howland, Shanshan W., Ng, Lai Guan, Saltel, Frdric, Castel, David, Grill, Jacques, Minard, Veronique, Albani, Salvatore, Chan, Jerry K. Y., Thion, Morgane Sonia, Jung, Sang Yong, Wenk, Markus R., Pouladi, Mahmoud A., Pasqualini, Claudia, Angeli, Veronique, Cexus, Olivier N. F., Ginhoux, Florent
Issue&Volume: 2023-11-01
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 tissues2,3,4,5,6. The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development7,8,9,10. However, current approaches do not incorporate microglia or address their role in organoid maturation11,12,13,14,15,16,17,18,19,20,21. 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.
來源：科學(xué)網(wǎng)
原標(biāo)題：iPS細(xì)胞衍生的小膠質(zhì)細(xì)胞通過膽固醇轉(zhuǎn)移促進(jìn)大腦類器官成熟
作者：小柯
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