Integrin Clustering Is Driven by Mechanical Resistance from the Glycocalyx and the Substrate

Integrins have emerged as key sensory molecules that translate chemical and physical cues from the extracellular matrix (ECM) into biochemical signals that regulate cell behavior. Integrins function by clustering into adhesion plaques, but the molecular mechanisms that drive integrin clustering in response to interaction with the ECM remain unclear. To explore how deformations in the cell-ECM interface influence integrin clustering, we developed a spatial-temporal simulation that integrates the micro-mechanics of the cell, glycocalyx, and ECM with a simple chemical model of integrin activation and ligand interaction. Due to mechanical coupling, we find that integrin-ligand interactions are highly cooperative, and this cooperativity is sufficient to drive integrin clustering even in the absence of cytoskeletal crosslinking or homotypic integrin-integrin interactions. The glycocalyx largely mediates this cooperativity and hence may be a key regulator of integrin function. Remarkably, integrin clustering in the model is naturally responsive to the chemical and physical properties of the ECM, including ligand density, matrix rigidity, and the chemical affinity of ligand for receptor. Consistent with experimental observations, we find that integrin clustering is robust on rigid substrates with high ligand density, but is impaired on substrates that are highly compliant or have low ligand density. We thus demonstrate how integrins themselves could function as sensory molecules that begin sensing matrix properties even before large multi-molecular adhesion complexes are assembled.

整合素（Integrins）已被证实为一类关键的感知分子，能够将来自细胞外基质（extracellular matrix, ECM）的化学与物理信号转换为调控细胞行为的生化信号。整合素通过聚集形成黏着斑（adhesion plaques）发挥功能，但驱动整合素在与ECM结合后发生聚集的分子机制仍不明确。为探究细胞-ECM界面的形变如何影响整合素聚集，我们构建了一套时空模拟模型，该模型将细胞、糖萼（glycocalyx）与ECM的微观力学特性，与整合素激活及配体相互作用的简化化学模型相结合。由于机械耦合作用，我们发现整合素与配体的相互作用具有高度协同性，且该协同性足以驱动整合素聚集，即便不存在细胞骨架交联或整合素自身的同源相互作用。糖萼在很大程度上介导了这一协同效应，因此可能是整合素功能的关键调控因子。值得注意的是，该模型中的整合素聚集可自然响应ECM的化学与物理特性，包括配体密度、基质刚度以及配体与受体的化学亲和力。与实验观测结果一致，我们发现整合素聚集在高配体密度的刚性基底上表现稳定，但在高度柔顺或配体密度较低的基底上则会受到抑制。综上，我们证实了整合素自身可作为感知分子，甚至在大型多分子黏着复合物组装完成之前，就能够开始感知基质的特性。