Generation of vascularized brain organoids to study neurovascular interactions.
Generation of vascularized brain organoids to study neurovascular interactions.
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生成血管化脑类器官以研究神经血管相互作用
DOI：
10.7554/elife.76707
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发表时间：
2022-05-04
期刊：
影响因子：
7.7
通讯作者：
Luo, Zhen-Ge
中科院分区：
文献类型：
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作者：
Sun, Xin-Yao;Ju, Xiang-Chun;Li, Yang;Zeng, Peng-Ming;Wu, Jian;Zhou, Ying-Ying;Shen, Li-Bing;Dong, Jian;Chen, Yue-Jun;Luo, Zhen-Ge
脑类器官已被用来概括大脑发育和相关疾病的过程。然而，调节神经发生和大脑疾病的脉管系统的缺乏限制了大脑类器官的实用性。在本研究中，我们分别诱导血管和脑类器官，然后将两种类型的类器官融合在一起以获得血管化的脑类器官。融合的大脑类器官被植入了坚固的血管网络样结构，并表现出神经祖细胞数量增加，这与血管调节神经发育的可能性相符。融合类器官还含有功能性血脑屏障样结构，以及小胶质细胞（大脑中的一种特定免疫细胞群）。合并的小胶质细胞对融合脑类器官的免疫刺激做出积极反应，并表现出吞噬突触的能力。因此，本研究中建立的融合类器官可以在体外模拟神经元和非神经元成分之间的相互作用，特别是脉管系统和小胶质细胞生态位。了解器官的形成方式及其细胞的行为方式对于寻找发育障碍的原因和治疗方法以及了解某些疾病至关重要。然而，研究活体动物或人类的大多数器官在技术上是困难的、昂贵的和侵入性的。为了解决这个问题，科学家们开发了一种名为“类器官”的模型，可以在实验室中使用干细胞来概括器官的发育。这些模型比活体器官更容易研究和操作。脑类器官已被用来重现大脑的形成以及发育性、退行性和精神性脑部疾病，例如小头畸形、自闭症和阿尔茨海默病。然而，这些大脑类器官缺乏为活体大脑提供营养并调节其发育的脉管系统（血管网络），而脉管系统在脑部疾病中发挥着重要作用。部分由于缺乏血管，大脑类器官也不会形成血脑屏障，这种结构可以阻止血液中的某些内容物，包括病原体、毒素甚至某些药物进入大脑。这些特征限制了现有大脑类器官的实用性。为了克服这些限制，Sun，Ju 等人。独立开发了脑类器官和血管类器官，然后将它们融合在一起以获得血管化的脑类器官。这些融合类器官形成了一个强大的血管网络，与脑细胞很好地结合在一起，并且比未融合的脑类器官产生了更多的神经细胞前体细胞。这一结果与血管可以调节大脑发育的观点是一致的。对融合类器官的分析表明，它们含有类似于血脑屏障的结构，以及小胶质细胞（大脑特有的免疫细胞）。当暴露于脂多糖（某些细菌细胞壁的成分）时，这些细胞通过在融合类器官中启动免疫反应来做出反应。值得注意的是，小胶质细胞还能够吞噬脑细胞之间的连接，这是大脑形成正确结构和正常工作所必需的过程。孙菊等人。开发了一种新的类器官系统，研究大脑和循环系统之间相互作用的研究人员将对此产生广泛的兴趣。融合类器官中脑血屏障样结构的发展也可以促进能够跨越这一屏障的药物的开发，从而更容易治疗影响大脑的某些疾病。完善该模型以使融合类器官在实验室中生长更长时间，并向系统添加血流将是建立该系统的下一步。
Brain organoids have been used to recapitulate the processes of brain development and related diseases. However, the lack of vasculatures, which regulate neurogenesis and brain disorders, limits the utility of brain organoids. In this study, we induced vessel and brain organoids, respectively, and then fused two types of organoids together to obtain vascularized brain organoids. The fused brain organoids were engrafted with robust vascular network-like structures and exhibited increased number of neural progenitors, in line with the possibility that vessels regulate neural development. Fusion organoids also contained functional blood–brain barrier-like structures, as well as microglial cells, a specific population of immune cells in the brain. The incorporated microglia responded actively to immune stimuli to the fused brain organoids and showed ability of engulfing synapses. Thus, the fusion organoids established in this study allow modeling interactions between the neuronal and non-neuronal components in vitro, particularly the vasculature and microglia niche. Understanding how the organs form and how their cells behave is essential to finding the causes and treatment for developmental disorders, as well as understanding certain diseases. However, studying most organs in live animals or humans is technically difficult, expensive and invasive. To address this issue, scientists have developed models called ‘organoids’ that recapitulate the development of organs using stem cells in the lab. These models are easier to study and manipulate than the live organs. Brain organoids have been used to recapitulate brain formation as well as developmental, degenerative and psychiatric brain conditions such as microcephaly, autism and Alzheimer’s disease. However, these brain organoids lack the vasculature (the network of blood vessels) that supplies a live brain with nutrients and regulates its development, and which has important roles in brain disorders. Partly due to this lack of blood vessels, brain organoids also do not develop a blood brain barrier, the structure that prevents certain contents of the blood, including pathogens, toxins and even certain drugs from entering the brain. These characteristics limit the utility of existing brain organoids. To overcome these limitations, Sun, Ju et al. developed brain organoids and blood vessel organoids independently, and then fused them together to obtain vascularized brain organoids. These fusion organoids developed a robust network of blood vessels that was well integrated with the brain cells, and produced more neural cell precursors than brain organoids that had not been fused. This result is consistent with the idea that blood vessels can regulate brain development. Analyzing the fusion organoids revealed that they contain structures similar to the blood-brain barrier, as well as microglial cells (immune cells specific to the brain). When exposed to lipopolysaccharide – a component of the cell wall of certain bacteria – these cells responded by initiating an immune response in the fusion organoids. Notably, the microglial cells were also able to engulf connections between brain cells, a process necessary for the brain to develop the correct structures and work normally. Sun, Ju et al. have developed a new organoid system that will be of broad interest to researchers studying interactions between the brain and the circulatory system. The development of brain-blood-barrier-like structures in the fusion organoids could also facilitate the development of drugs that can cross this barrier, making it easier to treat certain conditions that affect the brain. Refining this model to allow the fusion organoids to grow for longer times in the lab, and adding blood flow to the system will be the next steps to establish this system.