Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction.
Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction.
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分层水凝胶加速 iPSC 衍生的神经元成熟，并揭示 MeCP2 功能障碍引起的迁移缺陷。
DOI：
10.1073/pnas.1521255113
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发表时间：
2016
影响因子：
11.1
通讯作者：
Almutairi
中科院分区：
文献类型：
--
作者：
Zhang,Zhen-Ning;Freitas,BeatrizC;Qian,Hao;Lux,Jacques;Acab,Allan;Trujillo,CleberA;Herai,RobertoH;NguyenHuu,VietAnh;Wen,JessicaH;Joshi-Barr,Shivanjali;Karpiak,JeromeV;Engler,AdamJ;Fu,Xiang-Dong;Muotri,AlyssonR;Almutairi
使用患者来源的神经祖细胞（NPC）探测神经发育障碍中的广泛细胞表型可以通过3D测定来促进，因为2D系统不能完全概括脑中细胞的排列。在这里，我们开发了一种以前未识别的3D迁移和分化测定层状水凝胶，以检查这些过程是如何影响神经发育障碍，如Rett综合征。我们的软3D系统模拟大脑环境，并加速来自人类诱导多能干细胞（iPSC）衍生的NPC的神经元的成熟，在短短3周内产生电生理活性神经元。使用这个平台，我们揭示了甲基-CpG结合蛋白-2（MeCP 2）功能障碍对3D分层水凝胶中iPSC衍生的神经元迁移和成熟（减少的神经突生长和更少的突触）的基因型特异性作用。因此，这种3D系统扩大了可以在体外研究的神经表型的范围，包括那些受物理和机械刺激影响或需要多种细胞类型的特定排列的神经表型。
Probing a wide range of cellular phenotypes in neurodevelopmental disorders using patient-derived neural progenitor cells (NPCs) can be facilitated by 3D assays, as 2D systems cannot entirely recapitulate the arrangement of cells in the brain. Here, we developed a previously unidentified 3D migration and differentiation assay in layered hydrogels to examine how these processes are affected in neurodevelopmental disorders, such as Rett syndrome. Our soft 3D system mimics the brain environment and accelerates maturation of neurons from human induced pluripotent stem cell (iPSC)-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. Using this platform, we revealed a genotype-specific effect of methyl-CpG-binding protein-2 (MeCP2) dysfunction on iPSC-derived neuronal migration and maturation (reduced neurite outgrowth and fewer synapses) in 3D layered hydrogels. Thus, this 3D system expands the range of neural phenotypes that can be studied in vitro to include those influenced by physical and mechanical stimuli or requiring specific arrangements of multiple cell types.