The role of ECM-PIEZO1-axis-mediated mechanosensation in the central nervous system

Abstract

Central nervous system (CNS) diseases are characterized by high rates of disability and mortality, and their pathological progression is generally accompanied by abnormal remodeling of the extracellular matrix (ECM) composition and mechanical properties. The mechanosensitive cation channel PIEZO1 is widely expressed in neurons, microglia, astrocytes, oligodendrocytes, and endothelial cells of the CNS. It can precisely sense mechanical signals such as ECM stiffness, viscoelasticity, shear stress, and matrix protein cross-linking, and convert them into intracellular calcium signals and downstream biochemical reactions, thereby mediating the mechanobiological crosstalk between the ECM and cells and playing a key role in physiological processes such as neurodevelopment, synaptic plasticity, blood–brain barrier (BBB) homeostasis, neuroimmune regulation, and cell fate determination. In diseases such as Alzheimer’s disease (AD), ischemic stroke (IS), and multiple sclerosis (MS), abnormal stiffening or remodeling of the ECM can lead to excessive activation of PIEZO1, which, by regulating pathways such as nuclear factor-kappa B (NF-κB), Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), calcium/calmodulin-dependent protein kinase II (CaMKII), and glutathione peroxidase 4 (GPX4), exacerbates neuroinflammation, BBB disruption, myelin destruction, neuronal ferroptosis, and defective axonal regeneration. This article systematically reviews the cellular expression profile of PIEZO1 in the CNS, the ECM-mediated activation mechanisms, and downstream signaling networks. It elucidates the regulatory role of the ECM-PIEZO1 axis in both the physiological functions and typical diseases of the CNS, aiming to provide a theoretical basis and new insights for mechanobiological research into the mechanisms and targeted therapies of CNS diseases.