Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
School of Human Sciences, University of Western Australia, Perth, Western Australia, Australia.
Am J Physiol Cell Physiol. 2022 Jul 1;323(1):C236-C247. doi: 10.1152/ajpcell.00135.2022. Epub 2022 Jun 1.
Mechanical stress and the stiffness of the extracellular matrix are key drivers of tissue development and homeostasis. Aberrant mechanosensation is associated with a wide range of pathologies, including osteoarthritis. Matrix (or substrate) stiffness plays a major role in cell spreading, adhesion, proliferation, and differentiation. However, how specific cells sense substrate stiffness still remains unclear. The primary cilium is an essential cellular organelle that senses and integrates mechanical and chemical signals from the extracellular environment. We hypothesized that the primary cilium dynamically alters its length and position to fine-tune cell mechanosignaling based on substrate stiffness alone. We used a hydrogel system of varying substrate stiffness to examine the role of stiffness on cilia frequency, length, and centriole position as well as cell and nuclei area over time. Contrary to other cell types, we show that chondrocyte primary cilia shorten on softer substrates, demonstrating tissue-specific mechanosensing that is aligned with the tissue stiffness the cells originate from. We further show that stiffness determines centriole positioning to either the basal or apical membrane during attachment and spreading, with centrioles positioned toward the basal membrane on stiffer substrates. These phenomena are mediated by force generation actin-myosin stress fibers in a time-dependent manner. Finally, we show on stiff substrates that primary cilia are involved in tension-mediated cell spreading. We propose that substrate stiffness plays a role in cilia positioning, regulating cellular responses to external forces, and maybe a key driver of mechanosignaling-associated diseases.
机械应力和细胞外基质的刚性是组织发育和稳态的关键驱动因素。异常的机械感觉与广泛的病理学有关，包括骨关节炎。基质（或基底）的刚性在细胞扩展、黏附、增殖和分化中起着重要作用。然而，特定的细胞如何感知基底的刚性仍然不清楚。初级纤毛是一种重要的细胞细胞器，它可以感知和整合来自细胞外环境的机械和化学信号。我们假设初级纤毛可以根据基底的刚性动态地改变其长度和位置，以微调细胞的机械信号转导。我们使用不同基底刚性的水凝胶系统来研究基底刚性对纤毛频率、长度和中心粒位置以及细胞和核面积的影响。与其他细胞类型相反，我们发现软骨细胞的初级纤毛在较软的基底上变短，这表明了组织特异性的机械感觉，与细胞起源的组织刚性一致。我们进一步表明，刚性决定了附着和扩展过程中中心粒在基底或顶膜的定位，在较硬的基底上，中心粒定位在基底膜上。这些现象是通过力产生的肌动球蛋白应力纤维以时间依赖性的方式介导的。最后，我们在硬基底上表明，初级纤毛参与张力介导的细胞扩展。我们提出，基底刚性在纤毛定位中起作用，调节细胞对外部力的反应，并且可能是机械信号相关疾病的关键驱动因素。
