The Role of Extracellular Matrix Stiffness in Regulating Cellular Behavior and Disease Progression
CHEN Xiying, YI Li, LI Shucan, HU Yiwen, XIE Shanshan*
The ECM (extracellular matrix) is a crucial structural component outside the cell, providing not only physical support to tissues but also regulating cellular behavior through biochemical and mechanobiological signals. Recent studies have shown that ECM stiffness, as a key biophysical property, significantly influences fundamental biological processes such as cell morphology, proliferation, differentiation, migration, metabolism. Cells sense ECM stiffness through mechanosensors including integrins, talin, and vinculin, followed by the actin cytoskeleton-nuclear cytoskeleton mechanotransduction pathway, and regulate gene expression by activating key signaling pathways like YAP (Yes-associated protein)/TAZ (transcriptional coactivator with PDZ-binding motif), thereby determining cell fate. Changes in ECM stiffness play essential roles in both physiological and pathological processes. For example, during embryonic development and tissue homeostasis, ECM stiffness dictates stem cell differentiation and influences the mechanical coordination of cell populations. In pathological conditions such as cancer, organ fibrosis, and cardiovascular diseases, abnormal ECM stiffening or degradation drives disease progression by promoting ECM remodeling, altering cell plasticity, and reprogramming the immune microenvironment. Moreover, ECM stiffness can impact the efficacy of cancer immunotherapy by inhibiting T-cell infiltration and affecting drug permeability. Consequently, ECM-targeted intervention strategies, such as ECM softening therapies that are modulated by matrix metalloproteinases, are emerging as promising approaches in precision and personalized medicine. In the future, integrating single-cell omics, spatial transcriptomics, and biomechanical analysis will help unravel the dynamic changes in ECM mechanical signaling within the tissue microenvironment. This will facilitate the construction of a spatiotemporal atlas of ECM-cell interactions and provide innovative strategies for the diagnosis and treatment of major diseases.
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