Sun Lijuan, Xie Yafan, Zuo Zhaoyan, Liu Jian, Yang Jiaqi, Ali Iqra, Peng Qin, Qiu Juhui
Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College, Chongqing University, Chongqing 400030, China.
Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen 518132, China.
Biomater Res. 2025 Sep 18;29:0256. doi: 10.34133/bmr.0256. eCollection 2025.
The interplay between nuclear architecture and extracellular matrix stiffness orchestrates cell fate decisions, yet the molecular mechanisms remain poorly defined. Here, we investigate the role of Lamin A (), a nuclear structural protein whose expression correlates with tissue stiffness, in regulating cellular differentiation and fate decision. Using myoblasts and fibroblasts as models, it was observed that cells with low expression showed that higher cell deformation elevated expression of neurological genes and exhibited potential for differentiation into a neural-like fate. CUT&Tag sequencing of -knockdown cells revealed a reduction in the size of Lamin B1-associated domains, with enhanced Lamin B1 binding at muscle-related genes ( and ) and diminished binding at the neural gene , suggesting that changes in gene expression are associated with alterations in chromatin structure. Further analysis identified the dissolution of H3K9me2/3-labeled heterochromatin regions and their redistribution in the nucleoplasm following inhibition. Soft substrates (0.2 kPa) amplify the neural differentiation capacity in -knockout cells. Additionally, retinoic acid was shown to enhance the expression of neurologically related genes by suppressing expression. These findings reveal a novel substrate stiffness-induced mechanism by which Lamin A regulates cell fate transitions and provide a new approach for neural cell generation.
核结构与细胞外基质硬度之间的相互作用协调着细胞命运的决定，但其分子机制仍不清楚。在这里，我们研究核纤层蛋白A（Lamin A）的作用，它是一种核结构蛋白，其表达与组织硬度相关，在调节细胞分化和命运决定方面发挥作用。以成肌细胞和成纤维细胞为模型，观察到低表达的细胞显示出较高的细胞变形增加了神经基因的表达，并表现出分化为神经样命运的潜力。对Lamin A敲低细胞进行CUT&Tag测序发现，与核纤层蛋白B1（Lamin B1）相关的结构域大小减小，在肌肉相关基因（MyoD和Myf5）处Lamin B1结合增强，而在神经基因NeuroD处结合减少，这表明基因表达的变化与染色质结构的改变有关。进一步分析发现，抑制Lamin A后，H3K9me2/3标记的异染色质区域溶解并在核质中重新分布。软基质（0.2 kPa）增强了Lamin A敲除细胞的神经分化能力。此外，视黄酸通过抑制Lamin A表达来增强神经相关基因的表达。这些发现揭示了一种新的底物硬度诱导的机制，通过该机制Lamin A调节细胞命运转变，并为神经细胞生成提供了一种新方法。
