Biophysical Regulations of Epigenetic State and Notch Signaling in Neural Development Using Microgroove Substrates.
Biophysical Regulations of Epigenetic State and Notch Signaling in Neural Development Using Microgroove Substrates.
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DOI：
10.1021/acsami.2c01996
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发表时间：
2022-07-13
影响因子：
9.5
通讯作者：
Stevens, Molly M.
中科院分区：
文献类型：
--
作者：
Hsu, Chia-Chen;Serio, Andrea;Gopal, Sahana;Gelmi, Amy;Chiappini, Ciro;Desai, Ravi A.;Stevens, Molly M.
关键词：
最近的一些研究表明，表面形貌如何改变不同类型干细胞的行为和分化模式。虽然确切的机制和分子途径仍不清楚，一致的部分文献指出，核重塑引起的表观遗传变化。在这项研究中，我们研究了在聚二甲基硅氧烷微槽（3和10 μm深的槽）上培养时来自人类多能干细胞的临床相关神经群体的行为，以研究其分化能力和功能行为的机制。我们的研究结果表明，微槽增强细胞排列，修改核的几何形状，并显着增加细胞的刚度，我们能够测量在高分辨率的光学和电子显微镜，扫描离子电导显微镜（SICM），原子力显微镜（AFM）结合定量图像分析。微槽促进了表观遗传景观的显着变化，如关键组蛋白修饰标记物的表达所揭示的。微槽上神经干细胞的主要行为变化是在微槽上的基础条件下神经元分化的增加。通过测量切割的Notch 1水平，我们发现微槽下调Notch信号传导。事实上，我们提出，微槽地形影响神经干细胞的分化潜力，通过几何隔离间接改变Notch信号，这种机制与地形依赖性表观遗传调节并行，以提高干细胞神经元分化。
A number of studies have recently shown how surface topography can alter the behavior and differentiation patterns of different types of stem cells. Although the exact mechanisms and molecular pathways involved remain unclear, a consistent portion of the literature points to epigenetic changes induced by nuclear remodeling. In this study, we investigate the behavior of clinically relevant neural populations derived from human pluripotent stem cells when cultured on polydimethylsiloxane microgrooves (3 and 10 μm depth grooves) to investigate what mechanisms are responsible for their differentiation capacity and functional behavior. Our results show that microgrooves enhance cell alignment, modify nuclear geometry, and significantly increase cellular stiffness, which we were able to measure at high resolution with a combination of light and electron microscopy, scanning ion conductance microscopy (SICM), and atomic force microscopy (AFM) coupled with quantitative image analysis. The microgrooves promoted significant changes in the epigenetic landscape, as revealed by the expression of key histone modification markers. The main behavioral change of neural stem cells on microgrooves was an increase of neuronal differentiation under basal conditions on the microgrooves. Through measurements of cleaved Notch1 levels, we found that microgrooves downregulate Notch signaling. We in fact propose that microgroove topography affects the differentiation potential of neural stem cells by indirectly altering Notch signaling through geometric segregation and that this mechanism in parallel with topography-dependent epigenetic modulations acts in concert to enhance stem cell neuronal differentiation.
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作者：
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