{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPIEZO1 is a mechanosensitive cation‐permeable channel that converts various forms of mechanical stimuli into intracellular Ca²⁺ signals, thereby orchestrating multiple aspects of tissue homeostasis. For example, in epithelial tissues, PIEZO1 senses stretch versus crowding to differentially trigger cell division or extrusion, ensuring proper barrier function; its activity can also be chemically modulated by agonists such as Yoda1, while in neural stem cells it couples mechanical cues to Ca²⁺‐dependent lineage specification."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the blood compartment, PIEZO1 plays a pivotal role in red blood cell (RBC) volume regulation and vascular homeostasis. Mechanical stretch–induced Ca²⁺ entry through PIEZO1 activates downstream channels (for example, the Gardos channel) to regulate RBC hydration, while gain‐of‐function mutations slow channel inactivation and lead to erythrocyte dehydration, as observed in conditions such as hereditary xerocytosis and dehydrated hereditary stomatocytosis. Moreover, in the vascular endothelium, PIEZO1-mediated Ca²⁺ influx stimulates ATP release and nitric oxide production to control vasodilation and blood pressure. Detailed patch-clamp studies have characterized its ion selectivity and kinetics, further highlighting its unique biophysical properties."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond blood and epithelium, PIEZO1 is essential for proper development and mechanoadaptation in multiple tissues. In the musculoskeletal system, it functions as a key mechanotransducer in osteoblasts for load-dependent bone formation and in myoblasts where it coordinates Ca²⁺ signals that regulate myotube formation and polarized cell fusion. PIEZO1 is also implicated in the development and function of connective tissues such as tendons – where its activity influences collagen cross-linking and stiffness – and in the formation of lymphatic structures, as evidenced by its mutations being linked to congenital lymphatic dysplasia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPIEZO1 is also a key player in cancer progression, cell migration, and immune regulation. In malignant contexts, aberrant PIEZO1 signaling has been linked to enhanced cell motility, invasiveness, and metastasis in diverse tumors including gliomas, lung, breast, gastric, colon, and oral cancers. Its mechanotransductive function influences the reorganization of the cytoskeleton and modulates integrin-dependent adhesion and downstream signaling—processes that underlie the altered migratory behavior of cancer cells and even impact T cell activation and myeloid cell immunosuppressive programming."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent work has begun to unravel additional regulatory layers that modulate PIEZO1 function. Membrane lipid composition—particularly the balance between saturated and polyunsaturated fatty acids—can tune its activation and inactivation kinetics, while biophysical studies have revealed a profound voltage sensitivity and a capacity for dynamic coupling to the cytoskeleton via interactions with the cadherin–β–catenin complex. These modulatory influences not only affect fundamental channel properties (such as gating kinetics and inactivation, as demonstrated via double-mutant analyses) but also impact downstream paracrine signaling in cardiac fibroblasts, platelet activation under shear stress, and even potential interactions with secreted regulatory peptides. Additional emerging studies have implicated PIEZO1 in iron metabolism via macrophage activity, in cellular adaptation to mechanical confinement, and even in candidate binding with factors such as TFF1."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "42"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "S A Gudipaty, J Lindblom, P D Loftus, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms9085"}], "href": "https://doi.org/10.1038/ncomms9085"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26333996"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26333996"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Viktor Lukacs, Jayanti Mathur, Rong Mao, et al. 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