The Significance of the Piezo1-Mediated Mechanotransduction Pathway in Normal Morphogenesis

Introduction

Morphogenesis—the process through which cells and tissues acquire their shape and spatial organization during development—is central to establishing the structure and function of multicellular organisms (Chan et al., 2019). While classical developmental biology has emphasized genetic and biochemical regulation, it is now clear that mechanical cues from the physical microenvironment are equally critical determinants of cell fate, tissue patterning, and organogenesis (Hannezo and Heisenberg, 2019; Trushko et al., 2020). Over the past two decades, the integration of mechanical forces into developmental frameworks has reshaped our understanding of how tissue architecture is orchestrated.

Mechanical inputs such as compression, stretch, shear stress, and extracellular matrix stiffness govern essential cellular behaviors, including proliferation, differentiation, migration, and apoptosis. These forces are especially influential during embryogenesis, where rapid cell division, tissue folding, and organ formation generate dynamic and heterogeneous physical environments (Agarwal and Zaidel-Bar, 2021). Cells convert such forces into biochemical responses through mechanotransduction, a process that modulates gene expression and cellular behavior to coordinate developmental events (Piccolo et al., 2022). Despite significant conceptual progress, the molecular mechanisms by which cells sense and transduce mechanical signals during morphogenesis remained incompletely understood for many years (Novev et al., 2021).

A major breakthrough came with the discovery of the Piezo family of mechanosensitive ion channels, particularly Piezo1. Identified by Patapoutian and colleagues in 2010, Piezo1 is a large transmembrane protein forming a mechanically gated, nonselective cation channel (Coste et al., 2010). Unlike classical mechanoreceptors that rely on accessory structures or secondary messengers, Piezo1 is directly activated by membrane tension, enabling rapid and sensitive mechanical signal detection (Du et al., 2024). Since its discovery, Piezo1 has been identified in diverse tissues—including cardiovascular, neural, and epithelial systems—where it mediates key developmental processes such as vascular morphogenesis, neural tube formation, and epithelial homeostasis (Coste and Delmas, 2024; Zhong et al., 2018; Zong et al., 2023).

The significance of Piezo1-mediated mechanotransduction extends beyond force detection. Emerging evidence indicates that Piezo1 serves as a central regulator of morphogenetic programs by coupling mechanical cues to downstream pathways, particularly calcium signaling, MAPK activation, and YAP/TAZ-dependent transcription (Liu et al., 2021; Tao et al., 2019). Consistently, impaired Piezo1 function has been linked to a range of developmental abnormalities across multiple organ systems (Jiang et al., 2025).

Despite growing interest in Piezo biology, a comprehensive synthesis focusing specifically on Piezo1’s contributions to morphogenesis across tissues remains limited. This review addresses that gap by summarizing current knowledge of Piezo1’s molecular structure, mechanogating principles, developmental expression patterns, and downstream signaling mechanisms. We highlight how Piezo1 integrates mechanical information during tissue morphogenesis, examine the developmental consequences of its dysregulation, and discuss unresolved questions—including stage-specific regulation, pathway crosstalk, and limitations of current experimental models. Finally, we outline how emerging technologies such as live imaging, organoid systems, and single-cell transcriptomics are advancing our understanding of Piezo1’s dynamic roles. Together, these insights provide a framework for future studies in developmental mechanobiology.

Structural Basis and Mechanogating Principles of Piezo1

Piezo1 is a large, evolutionarily conserved mechanosensitive cation channel that directly converts membrane deformation into biochemical signaling, thereby linking physical forces to developmental programs and tissue homeostasis (Li et al., 2025a). Unlike many other mechanosensors, Piezo1 is intrinsically gated by tension within the lipid bilayer, enabling fast and reversible activation independent of second-messenger systems (Guo and MacKinnon, 2017). This biophysical architecture positions Piezo1 as a primary detector of mechanical inputs across diverse developmental contexts.

Structural Organization of Piezo1 Protein

Cryo-electron microscopy has revealed Piezo1 as a homotrimeric complex whose three curved, blade-like subunits bend the surrounding membrane into a dome-shaped configuration (Jiang et al., 2021; Li et al., 2025a). This membrane indentation is thought to underlie the channel’s exquisite sensitivity to changes in bilayer tension. Each subunit contains an array of transmembrane helices that form extended peripheral repeats mechanically coupled to an intracellular “beam” and associated anchor elements (Fig. 1). Together, these components are proposed to transmit force from the curved blades toward a centrally located pore module that mediates ion permeation.

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FIG. 1.

Schematic representation of the Piezo1 structure adapted from EMDB entry EMD-39219 (Electron Microscopy Data Bank) (Shan et al., 2025).

Although high-resolution structures now provide a detailed architectural framework, the precise conformational transitions that propagate membrane tension toward the pore remain incompletely understood. Available structures depict distinct “relaxed” and “flattened’’ states of the peripheral blades, consistent with a lever-like gating mechanism. They also reveal lateral ion pathways and peripheral portals whose physiological contribution is still under study (Dixit et al., 2025). At the core of the trimer, Piezo1 forms a nonselective cation pore with high Ca²⁺ permeability. Calcium entry serves as the principal trigger for downstream mechanotransductive pathways—including MAPK, YAP/TAZ, and nuclear factor of activated T cells (NFAT) signaling—that regulate morphogenetic processes such as cell shape remodeling, migration, and lineage specification (Ferreira et al., 2025).

Despite rapid progress, important aspects of Piezo1 mechanogating remain unresolved. Lipid–protein interactions, particularly involving cholesterol, can shift activation thresholds and alter channel kinetics (Xiao, 2024) suggesting that membrane composition shapes mechanosensitivity in vivo. Moreover, regulatory proteins such as STOML3 modulate Piezo1 responsiveness, but the molecular basis of such modulation is only beginning to be defined (Qi et al., 2015). These outstanding questions highlight the need for integrative structural, biophysical, and developmental studies to fully understand how Piezo1 translates mechanical landscapes into morphogenetic outcomes.

Mechanistic Basis of Piezo1 Activation by Mechanical Force

Piezo1 responds to membrane stretch, shear stress, and other mechanical cues primarily through a force-from-lipids mechanism in which increased bilayer tension drives conformational rearrangements that open the pore (Fig. 2A). Structural studies reveal that tension-induced flattening of Piezo1’s curved blades is transmitted toward the central pore through lever-like intracellular elements, producing rapid activation consistent with cryo-EM snapshots of distinct gating states (Guo and MacKinnon, 2017; Zhao et al., 2018). This gating behavior generates transient Ca²⁺ influx, initiating mechanotransductive signaling pathways relevant to developmental processes (Sugimoto et al., 2023).

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FIG. 2.

Piezo1 gating and downstream signaling pathways. (A) Schematic representation of Piezo1 in its closed (left) and open (right) conformations. Mechanical forces induce channel opening, allowing Ca²⁺ influx across the membrane. (B) Ca²⁺ influx through Piezo1 activates multiple downstream pathways, including MAPK/ERK, YAP/TAZ, and NFAT, and interacts with Notch, Wnt/β-catenin, and BMP/TGF-β signaling to regulate proliferation, differentiation, and morphogenesis.

Although bilayer tension is sufficient for channel opening, cytoskeletal and extracellular matrix interactions can tune Piezo1 sensitivity. Disruption of cytoskeletal support lowers activation thresholds and modifies inactivation kinetics, demonstrating a modulatory contribution from force-from-filament pathways (Cox et al., 2016). Additional regulation arises from lipid composition, with phosphoinositides and membrane cholesterol shifting activation or inactivation profiles (Vasileva and Chubinskiy‐Nadezhdin, 2023). These factors highlight the context-dependent nature of Piezo1 gating, shaped by bilayer mechanics, cytoskeletal architecture, and local lipid environment.

Distinctions Between Piezo1 and Other Mechanosensitive Channels

Piezo1 exhibits structural and functional features that set it apart from other mechanosensitive ion channels. Unlike the relatively simple pentameric (MscL) or heptameric (MscS) architectures of bacterial channels, Piezo1 adopts a large trimeric, three-bladed sctgqtructure with extensive transmembrane organization that enables high-sensitivity detection of subtle mechanical forces in eukaryotic membranes (Ge et al., 2015; Saotome et al., 2018). Whereas MscL and MscS primarily operate as emergency “pressure-release valves” that open under extreme osmotic stress (Bass et al., 2002; Sukharev et al., 1994), Piezo1 integrates physiologically relevant mechanical inputs and contributes to morphogenesis, vascular development, and tissue homeostasis (Syeda et al., 2016).

Compared with Piezo1’s direct bilayer-tension gating, mammalian transient receptor potential (TRP) channels form tetrameric assemblies that respond to diverse chemical and physical cues and often rely on accessory proteins or second-messenger pathways for mechanosensitivity (Caterina et al., 1997). Piezo1, by contrast, opens directly in response to increases in membrane tension without requiring intermediary signaling steps, allowing rapid and robust Ca²⁺ influx (Guo and MacKinnon, 2017). Experimental evidence confirms that many TRP channels display indirect or multimodal activation mechanisms, whereas Piezo1 exhibits fast, mechanically driven gating with a near-linear relationship between applied tension and channel opening (Syeda et al., 2016). Table 1 summarizes the major structural and functional differences among mechanosensitive channels.

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Table 1.

Distinctions Between Piezo1 and Other Mechanosensitive Channels

Channel	Oligomeric state	TM domains per subunit	Main activation stimulus	Biological role	Accessory proteins	Ca2+ permeability	Gating kinetics	Model organism(s)	Reference
Piezo1	Trimer	38	Membrane tension (physiological range)	Morphogenesis, cell fate, homeostasis	Not required	High	Rapid (<1 ms)	Animals	(Coste et al., 2010, Syeda et al., 2016)
MscL/MscS	Pentamer/Heptamer	2/3	Extreme osmotic pressure (cell swelling/lysis)	Osmoprotection under stress	Not required	Low to moderate	Rapid (<1 ms)	Bacteria	(Bass et al., 2002, Sukharev et al., 1994)
TRP	Tetramer	6	Diverse: chemical, thermal, mechanical	Sensory transduction (pain, temp, etc.)	Often required	Variable (low to high)	Slow/Variable	Animals	(Caterina et al., 1997)

Taken together, these comparisons highlight fundamental differences in both structural complexity and mechanogating strategy. Piezo1’s unique trimeric architecture and direct force-from-lipids activation allow it to sense subtle mechanical gradients that shape developmental processes—functional domains not typically attributed to bacterial mechanosensitive channels or TRP family members. Nevertheless, unresolved questions remain regarding how lipid composition, cytoskeletal interactions, and regulatory proteins fine-tune Piezo1 sensitivity across tissues, underscoring the need for standardized assays and in vivo integration.

Expression and Distribution of Piezo1 During Development

Piezo1 displays dynamic, temporally regulated, and tissue-specific expression across multiple organ systems throughout vertebrate development. High-resolution analyses demonstrate robust Piezo1 mRNA and protein expression in neural progenitor domains of the developing mouse forebrain, particularly within the ventricular and subventricular zones during peak neurogenesis (E12.5–E18.5). Piezo1 is prominently localized in radial glial cells and migrating neuroblasts, with region- and stage-specific enrichment in structures such as the ganglionic eminences and developing cortex (Kim et al., 2024). Functional disruption of Piezo1 in these neural populations impairs neuroepithelial organization, reduces proliferative capacity, and leads to abnormal neuronal differentiation (Kim et al., 2024; Nourse et al., 2022).

Beyond the nervous system, Piezo1 is strongly expressed in vascular endothelial cells and the endocardium during key stages of cardiovascular development. Its expression is highest in regions exposed to shear stress, including the ventricular outflow tract, and is essential for vascular remodeling and embryonic viability—genetic deletion results in severe cardiovascular malformations and mid-gestation lethality (Ranade et al., 2014). Within the skeletal system, Piezo1 expression in chondrocytes is required for endochondral ossification and postnatal bone maintenance; conditional knockout in cartilage-forming cells causes reduced trabecular bone mass and increased skeletal fragility (Brylka et al., 2024).

Piezo1 is also broadly expressed in the epithelial and stromal compartments of the kidney, bladder, ureter, and reproductive tract, as well as in other tissues routinely exposed to mechanical forces (Dalghi et al., 2019). Nonetheless, accurate determination of its developmental expression patterns in some organs remains challenged by limitations in antibody specificity and detection sensitivity (Dalghi et al., 2019; Kim et al., 2024).

Additional developing organs also exhibit significant Piezo1 expression. In the embryonic and postnatal lung, Piezo1 is present in airway epithelial cells and may contribute to branching morphogenesis and mechanical ventilation responses, although its precise developmental functions remain to be fully elucidated (Zarychanski et al., 2012). In the skin, Piezo1 expression in keratinocytes implicates it in developmental tissue remodeling and wound healing processes extending into adulthood (Nourse et al., 2022; Zarychanski et al., 2012). Furthermore, Piezo1 is abundantly expressed in erythrocytes, where it regulates red blood cell volume; mutations in PIEZO1 are causative for hereditary xerocytosis, a dehydration-associated hemolytic anemia (Zarychanski et al., 2012). Although less comprehensively investigated than neural or cardiovascular systems, these findings underscore the broad physiological significance of Piezo1 and highlight the need for expanded developmental studies across additional organ systems. A concise overview of these developmental expression patterns is provided in Table 2.

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Table 2.

Summary of Tissue-Specific Expression, Developmental Timing, and Functional Phenotypes of Piezo1 in Vertebrate Organ Systems

Tissue/Organ	Embryonic expression zone/cells	Peak stage	Function/Phenotype (KO)	Detection methods	Reference
Forebrain (CNS)	Neural progenitor zones, cortex, glia	E12.5–E18.5	Impaired neurogenesis, neuroepithelial defects	ISH, IHC, scRNA-seq	(Kim et al., 2024, Nourse et al., 2022)
Cardiovascular	Endothelium, endocardium	E9–E11.5	Vascular defects, embryonic lethality	Reporter mice, IHC	(Ranade et al., 2014)
Skeleton/Cartilage	Growth plate chondrocytes, osteophytes	Postnatal	Bone loss, rib fractures	IHC, reporter mice	(Brylka et al., 2024)
Kidney/Urinary	Epithelium, stroma	Embryonic–adult	Broad expression, roles under study	Reporter mice, IHC	(Dalghi et al., 2019)
Lung	Airway epithelium	Embryonic–adult	Reported, developmental role under investigation	RNA-seq, IHC	(Zarychanski et al., 2012)
Skin	Keratinocytes, epidermis	Embryonic–adult	Wound healing, tissue remodeling	IHC, RNA-seq	(Nourse et al., 2022, Zarychanski et al., 2012)
Blood cells	Erythrocytes	Embryonic–adult	Cell volume regulation, hereditary xerocytosis	Genetic, functional	(Nourse et al., 2022)

Despite significant methodological advances—including reporter mouse models, single-cell transcriptomics, and improved antibody reagents—comparative analyses across species and developmental timepoints remain necessary, particularly to resolve inconsistencies in cell-type specificity and temporal expression. Overall, the tightly regulated developmental expression of Piezo1 enables essential mechanosensory roles across neural, vascular, skeletal, urinary, and several additional organ systems, although the full scope of its contributions to morphogenesis continues to emerge.

Piezo1-Dependent Signaling and Crosstalk with Developmental Pathways

Mechanical activation of Piezo1 produces a rapid Ca²⁺ influx that engages several major signaling pathways—most prominently the MAPK/ERK, YAP/TAZ, and calcineurin–NFAT axes—which convert mechanical forces into transcriptional programs controlling morphogenesis (Pathak et al., 2014). Piezo1-dependent ERK activation has been demonstrated in endothelial and neural progenitor systems, where it promotes proliferation, lineage progression, and tissue remodeling (Pathak et al., 2014; Sun et al., 2019). Mechanical activation of Piezo1 also modulates cytoskeletal tension in a manner that promotes YAP/TAZ nuclear localization and transcriptional output, linking Piezo1 activity to epithelial growth, tissue shaping, and morphogenetic pattern formation (Dupont et al., 2011). Rapid epithelial cell division triggered by mechanical stretch has similarly been shown to require Piezo1 activity (Gudipaty et al., 2017). Ca²⁺-dependent NFAT signaling contributes to endothelial proliferation and cardiovascular patterning, though its interaction with ERK and YAP/TAZ remains incompletely defined (Ranade et al., 2014). Collectively, these pathways illustrate how Piezo1 converts membrane-level mechanical cues into coordinated gene-expression programs that regulate cell-state transitions and tissue-level architecture.

Piezo1 also intersects with classical developmental pathways that help integrate mechanical information with biochemical signaling systems. During vascular morphogenesis, Piezo1-mediated Ca²⁺ influx modulates Notch signaling to influence vessel patterning and flow-responsive remodeling (Li et al., 2014). In neural progenitors, Piezo1 influences the stability and nuclear accumulation of β-catenin, thereby linking extracellular stiffness to Wnt/β-catenin-dependent progenitor maintenance (Segel et al., 2019). In epithelial tissues, Piezo1 cooperates with BMP/TGF-β pathway components to regulate branching morphogenesis and tubulogenic patterning, demonstrating how mechanical inputs and morphogens jointly shape tissue geometry (Happe and Engler, 2016). Together, these findings position Piezo1 as a central integrator of mechanical forces with canonical developmental pathways, coordinating morphogenesis across multiple systems (Fig. 2B).

Functional Roles of Piezo1 in Morphogenetic Processes

Piezo1 channels participate in multiple morphogenetic processes by converting mechanical forces into biochemical signals that regulate cell behavior and tissue shaping. Their activity has been implicated in vascular morphogenesis, neural tube formation, epithelial organization, and other mechanically regulated developmental events. Although a broad range of animal models and organoid systems has clarified major aspects of Piezo1 function, several uncertainties persist, including tissue-specific differences, potential compensation by other mechanosensors, and variability among species and developmental stages. Occasional context-dependent or conflicting findings further highlight the need for more refined comparisons across models to fully define the developmental roles of Piezo1 (Jin et al., 2024).

Vascular Morphogenesis: Angiogenesis and Vasculogenesis

Vascular morphogenesis emerges from the coordinated integration of biochemical cues and mechanical forces within the embryonic microenvironment. Angiogenesis—the sprouting of new vessels from preexisting vasculature—is initiated by pro-angiogenic factors such as VEGF, FGF, and TGF-β, which promote endothelial activation, tip-cell specification, directed migration, and proliferative expansion of stalk cells (Blanco and Gerhardt, 2013; Otrock et al., 2007). These collective behaviors guide the extension and stabilization of nascent branches to form functional vascular networks (Blanco and Gerhardt, 2013).

Vasculogenesis, in contrast, represents the de novo establishment of the vascular system through differentiation of mesoderm-derived angioblasts and generation of a primitive vascular plexus during early embryogenesis (Risau and Flamme, 1995). Although classically restricted to development, vasculogenic programs can reactivate under pathological postnatal conditions such as ischemia or cancer, reflecting stress-induced deployment of embryonic patterning mechanisms (Asahara and Kawamoto, 2004; Begg et al., 2011).

Piezo1 functions as the primary mechanosensor that connects mechanical stresses to Ca²⁺-dependent signaling pathways in endothelial cells (Fig. 3). Mechanical stimulation of Piezo1 swiftly increases intracellular Ca²⁺, activating the CaMKII–MEKK3–MEK5–ERK5 pathway to stimulate KLF2/4 expression, which regulates endothelial identity, vascular stability, and flow-responsive morphogenesis (Zheng et al., 2022). The concurrent Ca²⁺-dependent stimulation of MAPK pathways also facilitates endothelial proliferation and differentiation (Dela Paz and Frangos, 2018). Shear-stress-induced activation of Piezo1 also triggers a PI3K/AKT–AMPK–eNOS pathway that increases nitric oxide synthesis, thereby facilitating endothelial alignment, motility, and angiogenic remodeling (Dela Paz and Frangos, 2018; Porto Ribeiro et al., 2022).

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FIG. 3.

Piezo1-mediated signaling pathways in endothelial cells. Activation of Piezo1 by mechanical forces induces Ca²⁺ influx, triggering downstream signaling via MEKK3/ERK5, CaMKII, and AMPK–eNOS cascades. Concurrently, Piezo1 modulates ADAM10-dependent Notch cleavage, leading to NICD release and KLF2/4 activation, thereby promoting vascular morphogenesis, angiogenesis, and endothelial differentiation.

Besides these cytoplasmic routes, Piezo1 regulates Notch signaling via ADAM10-mediated cleavage, which liberates NICD and strengthens transcriptional programs essential for vascular morphogenesis and angiogenesis. Loss-of-function (LoF) mutations in Piezo1 hinder sprouting, lumen development, and flow-induced remodeling in many model systems (Chen et al., 2021; Kang et al., 2019; Song and Munn, 2011). Notwithstanding these advancements, species-specific hemodynamic patterns and test variability result in a range of Piezo1-dependent abnormalities. Subsequent research employing uniform biomechanical stimulation and cross-species validation will be crucial to delineate the comprehensive mechanobiological framework regulating vascular development.

Neural Mechanomorphogenesis via Piezo1

Mechanical signals in the growing central nervous system create a complex biomechanical environment where Piezo1 functions as a primary mechanosensor, connecting extracellular structure to intracellular Ca²⁺-dependent signaling pathways (Fig. 4). In neural stem cells (NSCs), Piezo1-mediated Ca²⁺ influx governs lineage determination via YAP/TAZ activation, allowing NSCs to interpret substrate stiffness and microenvironmental pressures into neuronal differentiation choices (Pathak et al., 2014). Neurons demonstrate selective Piezo1 activation on pliable substrates, where mechanical sensitivity alters Ca²⁺ signaling dynamics and affects axonal behavior. Despite the downstream molecular architecture being inadequately characterized, increasing evidence suggests that Piezo1-dependent mechanotransduction plays a role in growth-cone regulation and may limit axonal extension in mechanically favorable environments, especially after injury-induced tissue softening (Zheng et al., 2023). Microglia depend on Piezo1 as their principal sensor for mechanical disturbances, including matrix stiffness and topographical irregularities. Activation of Piezo1 influences cytoskeletal remodeling and motility patterns, enhancing migration and phagocytic activity in response to mechanical heterogeneity (Hu et al., 2023; Zhu et al., 2023). Simultaneously, Piezo1 inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and reduces pro-inflammatory cytokine synthesis, facilitating a transition to an anti-inflammatory phenotype during tissue remodeling or neurodegenerative stress (Zhang et al., 2025). These findings establish Piezo1 as a pivotal regulator of microglial immunological and mechanical responses. Astrocytes employ Piezo1-dependent Ca²⁺ oscillations to modulate neuromodulatory outputs. The mechanical activation of Piezo1 induces ATP release, hence augmenting neural support functions and facilitating synaptic plasticity, whereas the absence of astrocyte-specific Piezo1 hinders hippocampus neurogenesis and learning-related plasticity (Hong et al., 2023). Collectively, these observations delineate a comprehensive mechanobiological framework wherein Piezo1 amalgamates mechanical stimuli with cell type-specific signaling pathways, encompassing NSC differentiation, neuronal growth regulation, microglial migration and immune modulation, as well as astrocyte-mediated neuromodulation.

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FIG. 4.

Mechanosensitive Piezo1 signaling in neural cells. Mechanical cues such as matrix stiffness or tissue roughness activate Piezo1 channels, inducing Ca²⁺ influx and triggering cell type-specific pathways: β-integrin/CaMKII–Mst1/2–Rac and NF-κB in microglia, YAP/TAZ in neural stem cells, NOS–PKG in neurons, and ATP signaling in astrocytes. These cascades regulate inflammatory response, differentiation, axonal growth, neurogenesis, and synaptic plasticity.

Epithelial Morphogenesis

Epithelial morphogenesis requires precise integration of mechanical inputs derived from cell–cell adhesion, extracellular matrix organization, and tissue-level tension. Piezo1, broadly expressed in epithelia of the bladder, colon, kidney, lung, and skin, acts as a key mechanosensory channel that couples these physical cues to Ca²⁺-dependent signaling programs governing epithelial folding, tubulogenesis, and homeostasis (Earley et al., 2022; Eid and Kurban, 2022; He et al., 2022).

During epithelial folding and invagination—processes essential for early gut development and branching morphogenesis—Piezo1 activation drives cytoskeletal remodeling and coordinated cell shape changes through rapid Ca²⁺ influx (Stewart and Davis, 2019). Genetic analyses further demonstrate that Piezo1-mediated mechanotransduction promotes stretch-induced proliferation in regions of low epithelial density, thereby supporting tissue expansion and remodeling during organogenesis (Eid and Kurban, 2022). Piezo1 also regulates homeostatic cell extrusion under mechanical crowding, ensuring epithelial integrity across zebrafish epidermis and mammalian tissues (Stewart and Davis, 2019).

Beyond these morphogenetic roles, Piezo1 is central to epithelial homeostasis by linking mechanical forces to pathways controlling proliferation, apoptosis, and differentiation. In skin, Piezo1-dependent mechanotransduction maintains epidermal stratification and barrier function, whereas its loss compromises regenerative capacity and alters epithelial architecture. Similarly, disrupted Piezo1 signaling leads to defects in tubulogenesis, epithelial complexity, and barrier integrity across multiple organ systems (Baumholtz et al., 2017; Rostami Ravari et al., 2025; Stewart and Davis, 2019).

Conditional knockout studies reinforce Piezo1 as a physiological regulator of epithelial biology. Deletion of Piezo1 in renal collecting duct epithelia impairs urinary osmolarity regulation during dehydration or fasting, highlighting its relevance to epithelial transport and fluid homeostasis (Martins et al., 2016). Dysregulation of Piezo1 also contributes to pathological epithelial behaviors: mechanical overstimulation enhances breast cancer cell migration and invasion through altered cytoskeletal mechanics, increased stiffness, and mechanosensitive promotion of invadopodia formation in response to compressive stress (Luo et al., 2022; So et al., 2024; Yu et al., 2021).

Despite these advances, several limitations persist. Current animal and organoid models do not fully replicate multicellular complexity, systemic cues, or species-specific features of human epithelia. Moreover, inconsistencies across platforms and species highlight the need for more physiologically relevant human-based systems (Roy Choudhury et al., 2021; Stewart and Davis, 2019). Progress in this area will rely on integrating organotypic models, single-cell and spatial transcriptomics, and multiomics approaches to delineate context-specific roles of Piezo1 and evaluate its therapeutic potential in epithelial developmental disorders and mechanopathologies.

Musculoskeletal Morphogenesis

Piezo1 is broadly expressed across musculoskeletal tissues and functions as a principal mechanosensitive cation channel that couples mechanical deformation to Ca²⁺-dependent biochemical signaling. Through this role, Piezo1 integrates extracellular physical cues with intracellular pathways that govern lineage specification, tissue growth, and structural remodeling during musculoskeletal development (Lei et al., 2024; Quiroga et al., 2020).

Muscle morphogenesis (myogenesis)

Mechanical activation of Piezo1—induced by membrane stretch, substrate deformation, or shear stress—drives Ca²⁺/calmodulin (CaM) signaling and subsequent activation of CaMKs, which stimulate JNK and p70S6K to engage the mTORC1–p70S6K axis, a key regulator of anabolic protein synthesis during myofiber growth (Lan et al., 2024). Convergence of CaMK and calcineurin pathways promotes nuclear translocation of NFAT and YAP, enhancing c-Myc expression, ribosomal biogenesis, and translational capacity to support myotube maturation (Goodman et al., 2015; Ito et al., 2018).

Piezo1-dependent Ca²⁺ influx also activates nitric oxide synthase (NOS), increasing NO levels and triggering the NO–cGMP–PKG cascade, which inhibits GSK-3 and relieves translational repression via eIF2B, while simultaneously stabilizing c-Myc under mechanical load (Mirzoev et al., 2021). In parallel, activation of the RhoA/ROCK axis promotes cytoskeletal tension and MLC2 phosphorylation, facilitating actomyosin assembly, myoblast alignment, and efficient fusion (Tsuchiya et al., 2018). Although the extent to which Piezo1 directly modulates mTORC1 through phospholipase D remains debated, evidence suggests a context-dependent interaction shaped by mechanical and metabolic state (Hornberger et al., 2006). Together, these Ca²⁺-regulated pathways position Piezo1 as a mechanotransductive hub coordinating CaMK/JNK/p70S6K, NO/GSK-3/eIF2B, and RhoA/ROCK signaling (Fig. 5), thereby shaping cytoskeletal architecture and promoting the growth and maturation of skeletal muscle fibers.

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FIG. 5.

Proposed Piezo1-dependent signaling pathways in skeletal muscle. Mechanical activation of Piezo1 induces Ca²⁺ influx, triggering CaM/CaMK- and calcineurin-dependent signaling that activates NFAT/YAP and c-Myc to promote translation initiation. Parallel activation of the CaMK–JNK–p70S6K and NOS/NO–GSK-3–eIF2B pathways supports protein synthesis, while Ca²⁺-driven RhoA/ROCK signaling mediates actomyosin assembly and myotube formation.

Bone signaling pathways regulated by Piezo1

Piezo1 is abundantly expressed in mesenchymal stem cells (MSCs), osteoblasts, and osteocytes, where it converts hydrostatic pressure, fluid shear stress (FSS), and substrate stiffness into Ca²⁺-dependent osteogenic signaling (Zhou et al., 2020). In MSCs, Piezo1 activation upregulates BMP2 via ERK1/2–p38 signaling and promotes osteogenic commitment while suppressing adipogenesis (Halloran et al., 2020; Sugimoto et al., 2017). Piezo1-mediated Ca²⁺ influx further activates the Ppp3a–NFAT–YAP–Wnt1–β-catenin axis, enhancing osteogenic gene expression (Ptgs2, Tnfrsf11b) while repressing Sost, linking mechanical signals to YAP1 activation and β-catenin stabilization (Zhou et al., 2020). In osteoblasts, mechanical activation of Piezo1 induces CaMKII and CREB phosphorylation, upregulating master transcription factors Runx2 and ATF4. Concurrent activation of AKT suppresses GSK3β, stabilizing β-catenin and facilitating Runx2-driven osteogenic transcription (Sun et al., 2019).

In osteocytes, Piezo1 senses matrix strain or FSS and triggers Ca²⁺-dependent AKT phosphorylation and YAP1 activation, promoting Ptgs2 and Tnfrsf11b expression while repressing Sost (Fig. 6) (Li et al., 2019). These responses regulate the OPG/RANKL axis, enhancing osteoanabolic remodeling. In vivo activation with Yoda1 increases cortical thickness and trabecular mass, emphasizing Piezo1’s osteogenic potential.

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FIG. 6.

Piezo1-mediated signaling in osteogenic differentiation and bone formation. Activation of Piezo1 by mechanical stimuli or Yoda1 induces Ca²⁺ influx and activates parallel pathways: Yap1/Wnt1/β-catenin promoting Ptgs2 and Tnfrsf11b expression, AKT/GSK3β–Runx2 enhancing osteogenic transcription, and CaMKII/CREB–ATF4 driving osteoblast differentiation. These cascades stimulate bone formation while repressing Sost expression.

Collectively, Piezo1 functions as a central mechanosensory node coordinating NFAT/YAP/β-catenin, CaMKII/CREB/Runx2/ATF4, and AKT/GSK3β pathways to direct lineage allocation, matrix remodeling, and osteogenesis. Its context-dependent engagement of these developmental programs may explain variability in reported phenotypes across experimental models.

Cardiovascular Morphogenesis

Cardiovascular morphogenesis fundamentally depends on the capacity of embryonic endothelial cells to sense and transduce mechanical forces. Piezo1 has emerged as a core mechanosensor in this context, responding to shear stress generated by blood flow and to membrane stretch to initiate downstream cascades essential for vascular and cardiac patterning. Piezo1 expression is high during early vascular development, and its mechanical activation produces Ca²⁺ influx that orchestrates endothelial alignment, migration, and remodeling of the nascent vasculature (Ranade et al., 2014; Shah et al., 2022; Wang et al., 2024).

LoF studies in mice demonstrate that Piezo1 is indispensable for cardiovascular development, as both global and endothelial-specific deletion result in embryonic lethality accompanied by severe defects in vascular remodeling, disorganization or absence of major vessels, and pericardial effusion (Ranade et al., 2014; Shah et al., 2022). Mechanistically, Ca²⁺ entry through Piezo1 activates calpain-dependent cytoskeletal remodeling and promotes the expression of matrix metalloproteinases such as MT1-MMP and MMP-2, facilitating angiogenic sprouting and expansion of vascular networks (Wang et al., 2024).

Beyond the blood vasculature, Piezo1 is essential for lymphatic morphogenesis. Endothelial-specific knockout disrupts valve formation and causes lymphatic dysplasia, while pathogenic PIEZO1 variants have been linked to hereditary lymphatic disorders in humans (Wang et al., 2024). Within the developing heart, Piezo1-mediated detection of shear stress and pressure modulates myocardial trabeculation and valve morphogenesis, processes highly sensitive to perturbations in hemodynamic forces (Cavallero et al., 2021). Piezo1 also interfaces with canonical developmental pathways, including Hippo–YAP and Notch, integrating biophysical and biochemical cues to guide endothelial proliferation, arterial–venous specification, and valve development (Cavallero et al., 2021; Wang et al., 2024).

Collectively, these findings position Piezo1 as a central regulator of cardiovascular morphogenesis, coordinating mechanical inputs with developmental signaling pathways to establish the spatial and temporal architecture of the heart, blood vessels, and lymphatic system.

Piezo1 Dysfunction in Morphogenesis

Conclusion

Piezo1 is a central mechanotransducer that converts membrane tension into Ca²⁺ signals to instruct normal morphogenesis. Through direct force-from-lipids gating, Piezo1 activates MAPK and YAP/TAZ (and in some settings NFAT) and intersects with Notch, Wnt/β-catenin, and BMP/TGF-β, thereby coordinating proliferation, polarity, migration, and differentiation. Convergent evidence across systems shows that Piezo1 enables vascular and lymphatic remodeling and valve formation; maintains neuroepithelial organization and neurogenesis; drives epithelial folding, tubulogenesis, and homeostatic extrusion; orchestrates myoblast fusion and alignment; and mediates load-responsive osteogenesis. Human genetics underscores developmental necessity: PIEZO1 GoF causes DHS, whereas LoF leads to primary lymphatic dysplasia.

Key open questions concern how lipid composition, cytoskeletal coupling, posttranslational modifications, and spatiotemporal expression tune channel gating and prioritize Piezo1-derived Ca²⁺ signals during morphogenesis. Methodological advances—high-resolution structural biology, live imaging, organoids and engineered tissues, single-cell atlases, and genetically encoded activity reporters—now enable causal tests in relevant contexts. Therapeutically, selective and context-aware modulation of Piezo1 holds promise for regenerative medicine and for vascular/lymphatic and musculoskeletal anomalies, but demands genotype-informed strategies and rigorous safety evaluation given the channel’s broad physiological roles.

Authors’ Contributions

R.R. led the conceptualization of the review, drafted the original manuscript, and conducted extensive editing. Y.M. assisted with the literature review and manuscript drafting, contributing significantly to the editing process. Z.R. and F.S. were involved in writing specific sections and revising the content for intellectual accuracy. They also conceptualized the review’s framework and provided critical feedback during revisions. Additionally, they supervised the structural development and offered substantial revisions to enhance clarity and depth. All authors approved the final manuscript, ensuring its readiness for publication.