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Engineering stem cell-derived 3D brain organoids in a perfusable organ-on-a-chip system

机译:在可灌注器官芯片系统中工程化干细胞衍生的3D脑器官

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Brain organoids derived from the self-organization of human induced pluripotent stem cells (hiPSCs) represent a new class of in vitro organ system for modeling brain development and diseases. However, engineering brain organoids in a biomimetic environment that is favorable for brain development remains challenging. In this work, we present a new strategy to generate hiPSCs-derived 3D brain organoids using an organ-on-a-chip system in a controlled manner. This system provides a biomimetic brain microenvironment by incorporating three-dimensional (3D) Matrigel, fluid flow and multicellular architectures of tissues that allows for extended 3D culture, in situ neural differentiation, and organization of brain organoids on a single device. The generated brain organoids display well-defined neural differentiation, regionalization and cortical organization under perfused culture conditions, which recapitulate the key features of early human brain development. Moreover, the brain organoids exhibit an enhanced expression of cortical layer markers (TBR1 and CTIP2) under perfused cultures as compared to that under static cultures on a Petri dish, indicating the role of mechanical fluid flow in promoting brain organogenesis. The simple and robust brain organoids-on-a-chip system may open new avenues for various stem cell-based organoids engineering and its application in developmental biology and human disease studies.
机译:从人类诱导的多能干细胞(hiPSC)的自组织产生的脑类器官代表了一种新型的体外器官系统,用于模拟大脑发育和疾病。但是,在对大脑发育有利的仿生环境中工程化大脑类器官仍然具有挑战性。在这项工作中,我们提出了一种新策略,可通过芯片上的器官系统以受控方式生成hiPSC衍生的3D脑类器官。该系统通过结合三维(3D)基质胶,组织的流体流动和多细胞结构,提供了仿生的大脑微环境,从而可以扩展3D培养,原位神经分化和组织脑组织。单个设备。在灌注培养条件下,生成的脑类器官显示出明确的神经分化,区域化和皮质组织,从而概括了人类早期大脑发育的关键特征。此外,与皮氏培养皿上的静态培养相比,灌注培养下的大脑类器官显示出皮质层标记(TBR1和CTIP2)的增强表达,表明机械液流在促进大脑器官发生中的作用。简单而强大的片上大脑类器官系统可能会为各种基于干细胞的类器官工程及其在发育生物学和人类疾病研究中的应用开辟新途径。

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