Yu Jing, Huang Jianyong, Jansen John A, Xiong Chunyang, Walboomers X Frank
Center for BioMed-X Research, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, PR China; Department of Biomaterials, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing 100871, PR China.
J Mech Behav Biomed Mater. 2017 Aug;72:29-37. doi: 10.1016/j.jmbbm.2017.04.018. Epub 2017 Apr 14.
Experimental findings indicate that cell function and behavior such as cell growth, division, migration and differentiation, are subtly regulated via integrin-dependent cell adhesion. Cell adhesion is influenced by nanoscale ligand spacing and rigidity of extracellular substrates, as cell adhesion drops greatly when the ligand spacing is larger than ~60nm, and cell adhesion is stronger on stiff than soft substrates. However, how nanoscale ligand spacing and substrate stiffness jointly affect integrin clustering and hence nascent cell adhesion remains to be elucidated. To quantitatively investigate the phenomena and the underlying mechanochemical mechanism of integrin clustering modulated by ligand spacing and substrate stiffness, we introduced Monte Carlo simulations varying the values of ligand spacing and substrate stiffness. Moreover, the effects of integrin number, integrin binding free energy, integrin association free energy, and local ligand spacing were investigated. The simulation results showed that integrin clustering decreased sharply, when ligand spacing was relatively large such as d>60nm in the current simulations, regardless of substrate rigidities, though with close spacing, the clustering increased with the substrate stiffness. The investigation contributes to the goals of understanding and predicting experimental phenomena, directing and optimizing biomaterial design, and manipulating integrin-dependent cell-substrate adhesion in tissue engineering.
实验结果表明，细胞功能和行为，如细胞生长、分裂、迁移和分化，是通过整合素依赖的细胞黏附被精细调节的。细胞黏附受纳米级配体间距和细胞外基质刚性的影响，因为当配体间距大于约60nm时细胞黏附会大幅下降，并且细胞在刚性基质上的黏附比在柔软基质上更强。然而，纳米级配体间距和基质刚性如何共同影响整合素聚集以及新生细胞黏附仍有待阐明。为了定量研究由配体间距和基质刚性调节的整合素聚集现象及其潜在的机械化学机制，我们引入了蒙特卡罗模拟，改变配体间距和基质刚性的值。此外，还研究了整合素数量、整合素结合自由能、整合素缔合自由能和局部配体间距的影响。模拟结果表明，在当前模拟中，当配体间距相对较大（如d>60nm）时，无论基质刚性如何，整合素聚集都会急剧下降，不过在间距较小时，聚集会随着基质刚性的增加而增加。该研究有助于实现理解和预测实验现象、指导和优化生物材料设计以及在组织工程中操控整合素依赖的细胞-基质黏附的目标。
