A Micropatterned Human-Specific Neuroepithelial Tissue for Modeling Gene and Drug-Induced Neurodevelopmental Defects.
A Micropatterned Human-Specific Neuroepithelial Tissue for Modeling Gene and Drug-Induced Neurodevelopmental Defects.
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DOI：
10.1002/advs.202001100
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Toh YC
中科院分区：
文献类型：
--
作者：
Sahni G;Chang SY;Meng JTC;Tan JZY;Fatien JJC;Bonnard C;Utami KH;Chan PW;Tan TT;Altunoglu U;Kayserili H;Pouladi M;Reversade B;Toh YC
结构标准化的人多能干细胞（hPSC）衍生的神经胚胎组织的产生具有模拟早期神经发育缺陷的遗传和环境介质的潜力。目前的神经模式系统迄今为止集中在指导细胞命运规范时空，而不是形态发生过程。在这里，结构上可再现且高度组织化的神经上皮（NE）组织的形成是由hPSC指导的，其重现了与早期神经形成相关的形态发生细胞过程。这些包括具有连续的极化上皮和明显的内陷样折叠，其中原始外胚层细胞在获得NE命运时经历E-至-N-钙粘蛋白转换和顶端收缩。这是通过中内胚层的时空模式化来实现的，中内胚层引导相邻原始外胚层的发育和自组织进入NE。结果发现，内胚层细胞发出的TGFβ信号支持预期NE的组织折叠。在模型中唯一可实现的NE组织结构性畸形的评价使得能够检测患者来源的hPSC中的顶端收缩和细胞粘附功能障碍以及区分不同类别的神经管缺陷诱导药物。本文报道了一个可重复的和高度组织化的神经上皮（NE）组织的产生相结合的人多能干细胞（hPSC）micropatterning和时间序列的诱导协议，以指定NE细胞在空间并列中内胚层细胞。通过在微图案化NE模型中评估NE组织结构性发育障碍，我们可以成功地对基因和药物诱导的神经发育缺陷进行建模。
The generation of structurally standardized human pluripotent stem cell (hPSC)‐derived neural embryonic tissues has the potential to model genetic and environmental mediators of early neurodevelopmental defects. Current neural patterning systems have so far focused on directing cell fate specification spatio‐temporally but not morphogenetic processes. Here, the formation of a structurally reproducible and highly‐organized neuroepithelium (NE) tissue is directed from hPSCs, which recapitulates morphogenetic cellular processes relevant to early neurulation. These include having a continuous, polarized epithelium and a distinct invagination‐like folding, where primitive ectodermal cells undergo E‐to‐N‐cadherin switching and apical constriction as they acquire a NE fate. This is accomplished by spatio‐temporal patterning of the mesoendoderm, which guides the development and self‐organization of the adjacent primitive ectoderm into the NE. It is uncovered that TGFβ signaling emanating from endodermal cells support tissue folding of the prospective NE. Evaluation of NE tissue structural dysmorphia, which is uniquely achievable in the model, enables the detection of apical constriction and cell adhesion dysfunctions in patient‐derived hPSCs as well as differentiating between different classes of neural tube defect‐inducing drugs. This paper reports the generation of a reproducible and highly organized neuroepithelial (NE) tissue by combining human pluripotent stem cell (hPSC) micropatterning and a temporally sequenced induction protocol to specify NE cells in spatial juxtaposition to mesoendoderm cells. By evaluating NE tissue structural dysmorphia in the micropatterned NE model, we can successfully model gene‐ and drug‐induced neurodevelopmental defects.
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