Effects of early geometric confinement on the transcriptomic profile of human cerebral organoids.
Effects of early geometric confinement on the transcriptomic profile of human cerebral organoids.
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DOI：
10.1186/s12896-021-00718-2
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发表时间：
2021-10-12
影响因子：
3.5
通讯作者：
Keung AJ
中科院分区：
文献类型：
--
作者：
Sen D;Voulgaropoulos A;Keung AJ
人脑类器官（hCO）是有吸引力的系统，因为它们能够模拟重要的大脑区域和早期体内大脑发育的转录组学。迄今为止，它们已被用于了解遗传和可溶性因子对神经发育的影响。有趣的是，hCO的主要优势之一是它们提供了更好地模拟体内环境的三维性;然而，尽管有这个核心特征，但空间和机械特性如何调节hCO和神经发育仍不清楚。虽然已知生物物理因素如形状和机械力在干细胞分化、胚胎发生和神经发育中起着至关重要的作用，但大部分工作研究了二维系统或依赖于三维中天然发育组织的相关观察。使用hCOs来建立空间因素和神经发育之间的联系将需要使用新的方法，并且可以揭示脑器官发生的基本原理，并将hCOs作为实验模型进行改进。在这里，我们研究了早期几何限制对hCO分化过程中转录组变化的影响。使用定制的和可调的琼脂糖微孔平台，我们产生了不同形状的胚状体（EB），模拟胚胎发生和神经发育的几种结构，然后将这些EB进一步分化为全脑hCO。我们的结果表明，微孔对hCO向神经命运分化的能力没有产生负面的总体影响，并且对神经谱系特化存在明显的形状依赖性影响。特别是，我们观察到，非球形的形状显示出改变的神经发育动力学的迹象，有利于发展的内侧神经节隆起相关的大脑区域和细胞类型的皮质区域。转录组学分析表明这些机械转导效应可能是由整合素和Wnt信号转导介导的。这里提出的研究结果表明，在hCO的发展过程中的大脑区域规范的空间因素的作用。了解这些空间模式化因素不仅将提高对体内发育和分化的理解，而且还提供了重要的手柄，以推进和改善对体外应用的人类模型系统的控制。在线版本包含补充材料，可通过10.1186/s12896-021-00718-2获得。
Human cerebral organoids (hCO) are attractive systems due to their ability to model important brain regions and transcriptomics of early in vivo brain development. To date, they have been used to understand the effects of genetics and soluble factors on neurodevelopment. Interestingly, one of the main advantages of hCOs are that they provide three dimensionality that better mimics the in vivo environment; yet, despite this central feature it remains unclear how spatial and mechanical properties regulate hCO and neurodevelopment. While biophysical factors such as shape and mechanical forces are known to play crucial roles in stem cell differentiation, embryogenesis and neurodevelopment, much of this work investigated two dimensional systems or relied on correlative observations of native developing tissues in three dimensions. Using hCOs to establish links between spatial factors and neurodevelopment will require the use of new approaches and could reveal fundamental principles of brain organogenesis as well as improve hCOs as an experimental model. Here, we investigated the effects of early geometric confinements on transcriptomic changes during hCO differentiation. Using a custom and tunable agarose microwell platform we generated embryoid bodies (EB) of diverse shapes mimicking several structures from embryogenesis and neurodevelopment and then further differentiated those EBs to whole brain hCOs. Our results showed that the microwells did not have negative gross impacts on the ability of the hCOs to differentiate towards neural fates, and there were clear shape dependent effects on neural lineage specification. In particular we observed that non-spherical shapes showed signs of altered neurodevelopmental kinetics and favored the development of medial ganglionic eminence-associated brain regions and cell types over cortical regions. Transcriptomic analysis suggests these mechanotransducive effects may be mediated by integrin and Wnt signaling. The findings presented here suggest a role for spatial factors in brain region specification during hCO development. Understanding these spatial patterning factors will not only improve understanding of in vivo development and differentiation, but also provide important handles with which to advance and improve control over human model systems for in vitro applications. The online version contains supplementary material available at 10.1186/s12896-021-00718-2.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.8
作者：
Birey F;Andersen J;Makinson CD;Islam S;Wei W;Huber N;Fan HC;Metzler KRC;Panagiotakos G;Thom N;O'Rourke NA;Steinmetz LM;Bernstein JA;Hallmayer J;Huguenard JR;Paşca SP
通讯作者：
Paşca SP
影响因子：
64.8
作者：
Nikolaev, Mikhail;Mitrofanova, Olga;Lutolf, Matthias P.
通讯作者：
Lutolf, Matthias P.
影响因子：
56.9
作者：
Pellegrini, Laura;Bonfio, Claudia;Lancaster, Madeline A.
通讯作者：
Lancaster, Madeline A.
影响因子：
6.1
作者：
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通讯作者：
Khademhosseini, Ali