3D光聚合微结构支架影响间充质干细胞的核变形、核/细胞骨架蛋白组织和基因调控。

IF 6.6 3区 医学 Q1 ENGINEERING, BIOMEDICAL
Francesca Donnaloja, Manuela Teresa Raimondi, Letizia Messa, Bianca Barzaghini, Federica Carnevali, Emanuele Colombo, Davide Mazza, Chiara Martinelli, Lucia Boeri, Federica Rey, Cristina Cereda, Roberto Osellame, Giulio Cerullo, Stephana Carelli, Monica Soncini, Emanuela Jacchetti
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引用次数: 0

摘要

来自细胞外环境的机械刺激影响细胞形态和功能。最近,我们报道了在定制的3D微支架Nichoid中生长的间充质干细胞(MSCs)能够表达更高水平的干细胞标记物。事实上,Nichoid在临床翻译中是一种有趣的自体间充质干细胞扩增装置,似乎可以通过改变细胞内力传递来调节基因活性。为了证实这一假设,我们研究了机械转导相关的核机制,我们也用一种破坏肌动蛋白细胞骨架的药物治疗扩散细胞。我们在Nichoid培养的MSCs中观察到一个圆形的核形状,并将核曲率与转录因子的输入相关联。我们观察到在Nichoid中培养的细胞中有一个更均匀的常染色质分布,相对于扁平样品,对应于一个标准的玻璃盖。这些结果表明了一种不同的基因调控,我们通过RNA-seq分析证实了这一点,该分析显示了1843个基因的失调。我们还观察到低结构的层状网格,根据实施的分子动力学模拟,表明阻尼活性降低,从而支持细胞内力传递低的假设。此外,我们对层粘胶蛋白表达和空间组织的研究支持了Nichoid诱导的基因失调主要与力传递减少有关的假设。总之,我们的发现揭示了Nichoid对MSC行为的影响,这是通过机械操作控制干细胞的一步,从而为MSC转化为临床应用的新策略铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
3D photopolymerized microstructured scaffolds influence nuclear deformation, nucleo/cytoskeletal protein organization, and gene regulation in mesenchymal stem cells.

Mechanical stimuli from the extracellular environment affect cell morphology and functionality. Recently, we reported that mesenchymal stem cells (MSCs) grown in a custom-made 3D microscaffold, the Nichoid, are able to express higher levels of stemness markers. In fact, the Nichoid is an interesting device for autologous MSC expansion in clinical translation and would appear to regulate gene activity by altering intracellular force transmission. To corroborate this hypothesis, we investigated mechanotransduction-related nuclear mechanisms, and we also treated spread cells with a drug that destroys the actin cytoskeleton. We observed a roundish nuclear shape in MSCs cultured in the Nichoid and correlated the nuclear curvature with the import of transcription factors. We observed a more homogeneous euchromatin distribution in cells cultured in the Nichoid with respect to the Flat sample, corresponding to a standard glass coverslip. These results suggest a different gene regulation, which we confirmed by an RNA-seq analysis that revealed the dysregulation of 1843 genes. We also observed a low structured lamina mesh, which, according to the implemented molecular dynamic simulations, indicates reduced damping activity, thus supporting the hypothesis of low intracellular force transmission. Also, our investigations regarding lamin expression and spatial organization support the hypothesis that the gene dysregulation induced by the Nichoid is mainly related to a reduction in force transmission. In conclusion, our findings revealing the Nichoid's effects on MSC behavior is a step forward in the control of stem cells via mechanical manipulation, thus paving the way to new strategies for MSC translation to clinical applications.

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来源期刊
APL Bioengineering
APL Bioengineering ENGINEERING, BIOMEDICAL-
CiteScore
9.30
自引率
6.70%
发文量
39
审稿时长
19 weeks
期刊介绍: APL Bioengineering is devoted to research at the intersection of biology, physics, and engineering. The journal publishes high-impact manuscripts specific to the understanding and advancement of physics and engineering of biological systems. APL Bioengineering is the new home for the bioengineering and biomedical research communities. APL Bioengineering publishes original research articles, reviews, and perspectives. Topical coverage includes: -Biofabrication and Bioprinting -Biomedical Materials, Sensors, and Imaging -Engineered Living Systems -Cell and Tissue Engineering -Regenerative Medicine -Molecular, Cell, and Tissue Biomechanics -Systems Biology and Computational Biology
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