Mechanical forces are fundamental drivers of morphogenesis, yet the molecular mechanisms that convert these physical cues into transcriptional responses remain incompletely understood. This review synthesizes current evidence identifying the mechanosensitive ion channel Piezo1 as a master regulator of developmental processes. The structural and biophysical principles underlying Piezo1 function are highlighted, focusing on its trimeric architecture and force-from-lipids gating mechanism that directly couples membrane tension to Ca2+ influx. Its spatiotemporal expression during embryogenesis is reviewed, and the downstream pathways it activates are examined, including mitogen-activated protein kinase (MAPK) and yes-associated protein/transcriptional co-activator with PDZ-binding moti (YAP/TAZ), alongside crucial crosstalk with canonical morphogen signaling cascades such as Notch, Wntwingless/integrated signaling pathway (Wnt)/beta-catenin (β-catenin), and bone morphogenetic protein/transforming growth factor-beta (BMP/TGF-β). Functional studies across diverse model systems demonstrate that Piezo1 orchestrates conserved morphogenetic events, including vascular and lymphatic patterning, neurogenesis, epithelial morphogenesis, myoblast fusion, and osteogenesis. Human genetic data further underscore its nonredundant role, linking gain-of-function mutations to dehydrated hereditary stomatocytosis and loss-of-function mutations to primary lymphatic dysplasia. Collectively, these findings establish Piezo1 as an essential integrator of mechanical and biochemical signals, central to tissue patterning and organ formation. The review concludes by emphasizing Piezo1's therapeutic potential in regenerative medicine and developmental disorders, while also underscoring the challenges of targeting such a broadly influential mechanosensor.

Dehydrated hereditary stomatocytosis (DHSt) is a heterogeneous group of rare hemolytic disorders with autosomal dominant inheritance. A series of 20 cases demonstrates that early identification of DHSt can prevent unnecessary interventions and improve the management of anemia, iron overload, and other complications in pediatric and adult patients. The presence of elevated mean corpuscular hemoglobin concentration (MCHC) with resistant erythrocytes suggested a possible association with variants in PIEZO1. Patients with KCNN4 variants showed no clear signs of erythrocyte dehydration, but, as with PIEZO1, macrocytosis, hemolytic anemia, and iron overload were common manifestations. Las estomatocitosis hereditarias deshidratadas (DHSt) constituyen un grupo heterogéneo de trastornos hemolíticos raros con herencia autosómica dominante. Una serie de 20 casos revela cómo la identificación precoz de las DHSt puede evitar intervenciones innecesarias y mejorar el manejo de la anemia, la sobrecarga de hierro y otras complicaciones en pacientes pediátricos y adultos. La presencia de una concentración de hemoglobina corpuscular media (CHCM) elevada con eritrocitos resistentes sugirió una posible asociación con variantes en PIEZO1. Los pacientes con variantes en KCNN4 no mostraron signos claros de deshidratación eritrocitaria, pero, al igual que en PIEZO1, la macrocitosis, la anemia hemolítica y la sobrecarga de hierro fueron manifestaciones frecuentes.

Hereditary anemias encompass a genetically heterogeneous spectrum of disorders, often involving multi-locus inheritance, which can complicate clinical management and worsen disease severity. This study investigates the impact of the co-inheritance of SEC23B loss-of-function pathogenic variants, which lead to congenital dyserythropoietic anemia type II (CDA II), and PIEZO1 gain-of-function pathogenic variants, associated with dehydrated hereditary stomatocytosis type I (DHS1), on hematological parameters and iron metabolism. Among 583 patients with suspected hereditary anemia, 13 were found to carry both SEC23B and PIEZO1 variants, leading to a dual diagnosis of CDA II and DHS1. Compared to those with isolated CDA II, these patients exhibited a significantly higher absolute reticulocyte count and bone marrow responsiveness index, alongside an increased prevalence of elevated ferritin levels. Functional studies in Hep3B human hepatoma cells confirmed that SEC23B knockdown combined with PIEZO1 gain-of-function led to marked ferritin accumulation and reduced hepcidin expression, driven by altered BMP/SMAD signaling and ERK1/2 MAPK pathway. These findings demonstrate how multi-locus inheritance can modify disease severity, particularly by exacerbating iron overload. Our results underscore the clinical relevance of comprehensive genetic testing for enhanced risk stratification and personalized management of hereditary anemias.

Hereditary stomatocytosis represents a heterogeneous group of inherited erythrocyte membrane defects characterized by hemolytic anemia of variable degree, with alterations in cellular salt and water, ranging from dehydration to overhydration, and the presence of stomatocytes on peripheral blood smear. This condition encompasses various subtypes, each with distinct clinical and genetic features. The pathophysiology underlying these conditions involves altered red blood cell membrane properties, leading to impaired deformability and alterations in cation permeability and volume, causing increased susceptibility to hemolysis. Advancements in genetic testing have enabled the identification of some causative genes in the last years, such as PIEZO1, KCNN4, and ABCB6. These genetic discoveries have facilitated a deeper understanding of the molecular mechanisms underlying the pathogenesis and have paved the way for improved diagnostic accuracy and genetic counseling. This review provides an overview of the clinical presentation, pathophysiology, molecular genetics, diagnosis, and management strategies of hereditary stomatocytosis, highlighting recent advancements in the field of dehydrated hereditary stomatocytosis (DHS), or hereditary xerocytosis, and hepatic iron overload. This latter is directly associated with the physiological role of PIEZO1, the causative gene of DHS, at hepatic and macrophagic levels. Particularly, gain-of-function mutations in PIEZO1 account for a pleiotropic syndrome characterized by different phenotypes depending on the expression of PIEZO1 in multiple cells and tissues.