Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure.
Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure.
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DOI：
10.1016/j.cell.2016.04.032
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发表时间：
2016-05-19
期刊：
影响因子：
64.5
通讯作者：
Ming GL
中科院分区：
文献类型：
--
作者：
Qian X;Nguyen HN;Song MM;Hadiono C;Ogden SC;Hammack C;Yao B;Hamersky GR;Jacob F;Zhong C;Yoon KJ;Jeang W;Lin L;Li Y;Thakor J;Berg DA;Zhang C;Kang E;Chickering M;Nauen D;Ho CY;Wen Z;Christian KM;Shi PY;Maher BJ;Wu H;Jin P;Tang H;Song H;Ming GL
脑类器官是模拟器官发生的三维培养物，为研究人脑发育提供了一个新的平台。高成本、变异性和组织异质性限制了它们的广泛应用。在这里，我们开发了一种小型化的旋转生物反应器（SpinΩ），以从人类iPSC中产生前脑特异性类器官。这些类器官概括了人类皮质发育的关键特征，包括祖细胞区组织，神经发生，基因表达，特别是独特的人类特异性外放射状胶质细胞层。我们还开发了中脑和下丘脑类器官的方案。最后，我们采用前脑类器官平台来模拟寨卡病毒（ZIKV）暴露。定量分析揭示了非洲或亚洲ZIKV毒株对神经祖细胞的优先、生产性感染。ZIKV感染导致细胞死亡增加和增殖减少，导致类似于小头畸形的神经元细胞层体积减少。我们的大脑区域特异性类器官和SpinΩ共同为人类大脑发育和疾病建模以及包括潜在ZIKV抗病毒药物在内的化合物测试提供了一个可访问的通用平台。寨卡病毒优先感染早期皮质类器官中的神经祖细胞，使用具有成本效益的微型旋转生物反应器产生，导致增殖抑制，细胞死亡增加和类似小头畸形的宏观特征。
Cerebral organoids, three-dimensional cultures that model organogenesis, provide a new platform to investigate human brain development. High cost, variability and tissue heterogeneity limit their broad applications. Here we developed a miniaturized spinning bioreactor (SpinΩ) to generate forebrain-specific organoids from human iPSCs. These organoids recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and notably, a distinct human-specific outer radial glia cell layer. We also developed protocols for midbrain and hypothalamic organoids. Finally, we employed the forebrain organoid platform to model Zika virus (ZIKV) exposure. Quantitative analyses revealed preferential, productive infection of neural progenitors with either African or Asian ZIKV strains. ZIKV infection leads to increased cell death and reduced proliferation, resulting in decreased neuronal cell layer volume resembling microcephaly. Together, our brain region-specific organoids and SpinΩ provide an accessible and versatile platform for modeling human brain development and disease, and for compound testing including potential ZIKV antiviral drugs. Zika virus preferentially infects neural progenitors in early stage cortical organoids, generated using cost-effective miniaturized spinning bioreactors, resulting in suppressed proliferation, increased cell death, and macroscopic features resembling microcephaly.