RESUMEN
Distraction osteogenesis is widely used for bone tissue engineering. Mechanical stimulation plays a central role in the massive tissue regeneration observed during distraction osteogenesis. Although distraction osteogenesis has been a boon for patients with bone defects, we still have limited knowledge about the intrinsic mechanotransduction that converts physical forces into biochemical signals capable of inducing cell behavior changes and new tissue formation. In this review, we summarize the findings for mechanoresponsive factors, including cells, genes, and signaling pathways, during the distraction osteogenesis different phases. These elements function for coupling of osteogenesis and angiogenesis via the Integrin-FAK, TGF-ß/BMP, Wnt/ß-catenin, Hippo, MAPK, PI3K/Akt, and HIF-1α signaling pathways in a mechanoresponsive niche. The available evidence further suggests the existence of a balance between the epithelial-mesenchymal transition and mesenchymal-epithelial transition under hypoxic stress. We also briefly summarize the current in silico simulation algorithms and propose several future research directions that may advance understanding of distraction osteogenesis in the era of bioinformation, particularly the integration of artificial intelligence models with reliable single-cell RNA sequencing datasets. The objective of this review is to utilize established knowledge to further optimize existing distraction protocols and to identify potential therapeutic targets.
Asunto(s)
Mecanotransducción Celular , Osteogénesis por Distracción , Humanos , Osteogénesis por Distracción/métodos , Animales , Osteogénesis/fisiología , Regeneración Ósea/fisiología , Transducción de Señal , Ingeniería de Tejidos/métodos , Transición Epitelial-Mesenquimal/fisiologíaRESUMEN
Pulmonary fibrosis is a complex and intractable disease characterized by extracellular matrix accumulation and altered mechanical properties of lung tissue. Biomechanical properties are closely related to the development, progression, and treatment of tissue fibrosis. In this review, we summarized the changes in the pulmonary biomechanical microenvironment, highlight the role of mechanotransduction in pulmonary fibrosis, and describe recent clinical advances targeting mechanical signals to alleviate pulmonary fibrosis.
Asunto(s)
Matriz Extracelular , Mecanotransducción Celular , Fibrosis Pulmonar , Humanos , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/fisiopatología , Matriz Extracelular/metabolismo , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Transducción de Señal , AnimalesRESUMEN
Mechanical force is the basis of cardiovascular development, homeostasis, and diseases. The perception and response of mechanical force by the cardiovascular system are crucial. However, the molecular mechanisms mediating mechanotransduction in the cardiovascular system are not yet understood. PIEZO1, a novel transmembrane mechanosensitive cation channel known for its regulation of touch sensation, has been found to be widely expressed in the mammalian cardiovascular system. In this review, we elucidate the role and mechanism of PIEZO1 as a mechanical sensor in cardiovascular development, homeostasis, and disease processes, including embryo survival, angiogenesis, cardiac development repair, vascular inflammation, lymphangiogenesis, blood pressure regulation, cardiac hypertrophy, cardiac fibrosis, ventricular remodeling, and heart failure. We further summarize chemical molecules targeting PIEZO1 for potential translational applications. Finally, we address the controversies surrounding emergent concepts and challenges in future applications.
Asunto(s)
Sistema Cardiovascular , Canales Iónicos , Humanos , Animales , Sistema Cardiovascular/metabolismo , Canales Iónicos/metabolismo , Mecanotransducción Celular , Enfermedades Cardiovasculares/metabolismo , Mamíferos/metabolismoRESUMEN
The Caenorhabditis elegans HMP-2/HMP-1 complex, akin to the mammalian [Formula: see text]-catenin-[Formula: see text]-catenin complex, serves as a critical mechanosensor at cell-cell adherens junctions, transducing tension between HMR-1 (also known as cadherin in mammals) and the actin cytoskeleton. Essential for embryonic development and tissue integrity in C. elegans, this complex experiences tension from both internal actomyosin contractility and external mechanical microenvironmental perturbations. While offering a valuable evolutionary comparison to its mammalian counterpart, the impact of tension on the mechanical stability of HMP-1 and HMP-2/HMP-1 interactions remains unexplored. In this study, we directly quantified the mechanical stability of full-length HMP-1 and its force-bearing modulation domains (M1-M3), as well as the HMP-2/HMP-1 interface. Notably, the M1 domain in HMP-1 exhibits significantly higher mechanical stability than its mammalian analog, attributable to interdomain interactions with M2-M3. Introducing salt bridge mutations in the M3 domain weakens the mechanical stability of the M1 domain. Moreover, the intermolecular HMP-2/HMP-1 interface surpasses its mammalian counterpart in mechanical stability, enabling it to support the mechanical activation of the autoinhibited M1 domain for mechanotransduction. Additionally, the phosphomimetic mutation Y69E in HMP-2 weakens the mechanical stability of the HMP-2/HMP-1 interface, compromising the force-transmission molecular linkage and its associated mechanosensing functions. Collectively, these findings provide mechanobiological insights into the C. elegans HMP-2/HMP-1 complex, highlighting the impact of salt bridges on mechanical stability in [Formula: see text]-catenin and demonstrating the evolutionary conservation of the mechanical switch mechanism activating the HMP-1 modulation domain for protein binding at the single-molecule level.
Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Mecanotransducción Celular , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Animales , Caenorhabditis elegans/metabolismo , Mecanotransducción Celular/fisiología , Imagen Individual de Molécula , Unión Proteica , Cadherinas/metabolismo , Cadherinas/química , Cadherinas/genética , Uniones Adherentes/metabolismo , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/química , Proteínas del Citoesqueleto , alfa CateninaRESUMEN
Hair cell bundles consist of stereocilia arranged in rows of increasing heights, connected by tip links that transmit sound-induced forces to shorter stereocilia tips. Auditory mechanotransduction channel complexes, composed of proteins TMC1/2, TMIE, CIB2, and LHFPL5, are located at the tips of shorter stereocilia. While most components can interact with the tip link in vitro, their ability to maintain the channel complexes at the tip link in vivo is uncertain. Return, using mouse models, we show that an additional component, LOXHD1, is essential for keeping TMC1-pore forming subunits at the tip link but is dispensable for TMC2. Using SUB-immunogold-SEM, we showed that TMC1 localizes near the tip link but mislocalizes without LOXHD1. LOXHD1 selectively interacts with TMC1, CIB2, LHFPL5, and tip-link protein PCDH15. Our results demonstrate that TMC1-driven mature auditory channels require LOXHD1 to stay connected to the tip link and remain functional, while TMC2-driven developmental channels do not.
Asunto(s)
Mecanotransducción Celular , Proteínas de la Membrana , Animales , Ratones , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/fisiología , Estereocilios/metabolismo , Cadherinas/metabolismo , Cadherinas/genética , Proteínas Relacionadas con las Cadherinas , Ratones Noqueados , Femenino , Masculino , Ratones Endogámicos C57BL , Precursores de ProteínasRESUMEN
Tendons enable locomotion by transmitting high tensile mechanical forces between muscle and bone via their dense extracellular matrix (ECM). The application of extrinsic mechanical stimuli via muscle contraction is necessary to regulate healthy tendon function. Specifically, applied physiological levels of mechanical loading elicit an anabolic tendon cell response, while decreased mechanical loading evokes a degradative tendon state. Although the tendon response to mechanical stimuli has implications in disease pathogenesis and clinical treatment strategies, the cell signaling mechanisms by which tendon cells sense and respond to mechanical stimuli within the native tendon ECM remain largely unknown. Therefore, we explored the role of cell-ECM adhesions in regulating tendon cell mechanotransduction by perturbing the genetic expression and signaling activity of focal adhesion kinase (FAK) through both in vitro and in vivo approaches. We determined that FAK regulates tendon cell spreading behavior and focal adhesion morphology, nuclear deformation in response to applied mechanical strain, and mechanosensitive gene expression. In addition, our data reveal that FAK signaling plays an essential role in in vivo tendon development and postnatal growth, as FAK-knockout mouse tendons demonstrated reduced tendon size, altered mechanical properties, differences in cellular composition, and reduced maturity of the deposited ECM. These data provide a foundational understanding of the role of FAK signaling as a critical regulator of in situ tendon cell mechanotransduction. Importantly, an increased understanding of tendon cell mechanotransductive mechanisms may inform clinical practice as well as lead to the discovery of diagnostic and/or therapeutic molecular targets.
Asunto(s)
Mecanotransducción Celular , Ratones Noqueados , Tendones , Animales , Masculino , Ratones , Células Cultivadas , Matriz Extracelular/metabolismo , Quinasa 1 de Adhesión Focal/metabolismo , Quinasa 1 de Adhesión Focal/genética , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/genética , Adhesiones Focales/metabolismo , Mecanotransducción Celular/fisiología , Ratones Endogámicos C57BL , Transducción de Señal/fisiología , Tendones/metabolismo , Tendones/fisiología , Tendones/citología , FemeninoRESUMEN
Purpose: Glaucoma, one of the leading causes of irreversible blindness, is a common progressive optic neuropathy characterised by visual field defects and structural changes to the optic nerve head (ONH). There is extracellular matrix (ECM) accumulation and fibrosis of the lamina cribrosa (LC) in the ONH, and consequently increased tissue stiffness of the LC connective tissue. Integrins are cell surface proteins that provide the key molecular link connecting cells to the ECM and serve as bidirectional sensors transmitting signals between cells and their environment to promote cell adhesion, proliferation, and remodelling of the ECM. Here, we investigated the expression of αVß3 integrin in glaucoma LC cell, and its effect on stiffness-induced ECM gene transcription and cellular proliferation rate in normal (NLC) and glaucoma (GLC) LC cells, by down-regulating αVß3 integrin expression using cilengitide (a known potent αVß3 and αVß5 inhibitor) and ß3 integrin siRNA knockdown. Methods: GLC cells were compared to age-matched controls NLC to determine differential expression levels of αVß3 integrin, ECM genes (Col1A1, α-SMA, fibronectin, vitronectin), and proliferation rates. The effects of αVß3 integrin blockade (with cilengitide) and silencing (with a pool of four predesigned αVß3 integrin siRNAs) on ECM gene expression and proliferation rates were evaluated using both reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting in the human NLC cells cultured on soft (4 kPa) and stiff (100 kPa) substrate and in GLC cells grown on standard plastic plates. Results: αVß3 integrin gene and protein expression were enhanced (p < 0.05) in GLC cells as compared to NLC. Both cilengitide and siRNA significantly reduced αVß3 expression in GLC. When NLC were grown in the stiff substrate, cilengitide and siRNA also significantly reduced the increased expression in αVß3, ECM components, and proliferation rate. Conclusions: Here, we provide evidence of cilengitide- and siRNA-mediated silencing of αVß3 integrin expression, and inhibition of ECM synthesis in LC cells. Therefore, αVß3 integrin may be a promising target for the development of novel anti-fibrotic therapies for treating the LC cupping of the ONH in glaucoma.
Asunto(s)
Proliferación Celular , Glaucoma , Integrina alfaVbeta3 , Mecanotransducción Celular , Humanos , Integrina alfaVbeta3/metabolismo , Integrina alfaVbeta3/genética , Glaucoma/patología , Glaucoma/metabolismo , Glaucoma/genética , Matriz Extracelular/metabolismo , Disco Óptico/metabolismo , Disco Óptico/patología , Venenos de Serpiente , Persona de Mediana Edad , Masculino , Anciano , FemeninoRESUMEN
Piezo proteins have been identified as mechanosensitive ion channels involved in mechanotransduction. Several ion channel dysfunctions may be associated with diseases (including deafness and pain); thus, studying them is critical to understand their role in mechanosensitive disorders and to establish new therapeutic strategies. The current study investigated for the first time the expression patterns of Piezo proteins in zebrafish octavolateralis mechanosensory organs. Piezo 1 and 2 were immunoreactive in the sensory epithelia of the lateral line system and the inner ear. Piezo 1 (28.7 ± 1.55 cells) and Piezo 2 (28.8 ± 3.31 cells) immunopositive neuromast cells were identified based on their ultrastructural features, and their overlapping immunoreactivity to the s100p specific marker (28.6 ± 1.62 cells), as sensory cells. These findings are in favor of Piezo proteins' potential role in sensory cell activation, while their expression on mantle cells reflects their implication in the maintenance and regeneration of the neuromast during cell turnover. In the inner ear, Piezo proteins' colocalization with BDNF introduces their potential implication in neuronal plasticity and regenerative events, typical of zebrafish mechanosensory epithelia. Assessing these proteins in zebrafish could open up new scenarios for the roles of these important ionic membrane channels, for example in treating impairments of sensory systems.
Asunto(s)
Oído Interno , Canales Iónicos , Sistema de la Línea Lateral , Mecanotransducción Celular , Proteínas de Pez Cebra , Pez Cebra , Animales , Pez Cebra/metabolismo , Oído Interno/metabolismo , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Canales Iónicos/metabolismo , Canales Iónicos/genética , Sistema de la Línea Lateral/metabolismoRESUMEN
Mechanical forces affect periodontal health through multiple mechanisms. Normally, mechanical forces can boost soft and hard tissue metabolism. However, excessive forces may damage the periodontium or result in irreversible inflammation, whereas absence of occlusion forces also leads to tissue atrophy and bone resorption. We systemically searched the PubMed and Web of Science databases and found certain mechanisms of mechanical forces on immune defence, extracellular matrix (ECM) metabolism, specific proteins, bone metabolism, characteristic periodontal ligament stem cells (PDLSCs) and non-coding RNAs (ncRNAs) as these factors contribute to periodontal homeostasis. The immune defence functions change under forces; genes, signalling pathways and proteinases are altered under forces to regulate ECM metabolism; several specific proteins are separately discussed due to their important functions in mechanotransduction and tissue metabolism. Functions of osteocytes, osteoblasts, and osteoclasts are activated to maintain bone homeostasis. Additionally, ncRNAs have the potential to influence gene expression and thereby, modify tissue metabolism. This review summarizes all these mechanisms of mechanical forces on periodontal homeostasis. Identifying the underlying causes, this review provides a new perspective of the mechanisms of force on periodontal health and guides for some new research directions of periodontal homeostasis.
Asunto(s)
Homeostasis , Mecanotransducción Celular , Ligamento Periodontal , Periodoncio , Humanos , Periodoncio/metabolismo , Animales , Ligamento Periodontal/metabolismo , Matriz Extracelular/metabolismo , Estrés Mecánico , Enfermedades Periodontales/metabolismo , Enfermedades Periodontales/inmunología , ARN no Traducido/genética , ARN no Traducido/metabolismo , Células Madre/metabolismoRESUMEN
Cells sense and respond to mechanical forces through mechanotransduction, which regulates processes in health and disease. In single adhesive cells, mechanotransduction involves the transmission of force from the extracellular matrix to the cell nucleus, where it affects nucleocytoplasmic transport (NCT) and the subsequent nuclear localization of transcriptional regulators, such as YAP (also known as YAP1). However, if and how NCT is mechanosensitive in multicellular systems is unclear. Here, we characterize and use a fluorescent sensor of nucleocytoplasmic transport (Sencyt) and demonstrate that NCT responds to mechanical forces but not cell density in cell monolayers. Using monolayers of both epithelial and mesenchymal phenotype, we show that NCT is altered in response both to osmotic shocks and to the inhibition of cell contractility. Furthermore, NCT correlates with the degree of nuclear deformation measured through nuclear solidity, a shape parameter related to nuclear envelope tension. In contrast, YAP is sensitive to cell density, showing that the YAP response to cell-cell contacts is not via a mere mechanical effect of NCT. Our results demonstrate the generality of the mechanical regulation of NCT.
Asunto(s)
Transporte Activo de Núcleo Celular , Núcleo Celular , Mecanotransducción Celular , Transporte Activo de Núcleo Celular/fisiología , Núcleo Celular/metabolismo , Recuento de Células , Animales , Proteínas Señalizadoras YAP/metabolismo , Humanos , PerrosRESUMEN
Mechanotransduction, which is the integration of mechanical signals from the external environment of a cell to changes in intracellular signaling, governs many cellular functions. Recent studies have shown that the mechanical state of the cell is also coupled to the cellular circadian clock. To investigate possible interactions between circadian rhythms and cellular mechanotransduction, we have developed a computational model that integrates the two pathways. We postulated that translocation of the transcriptional regulators MRTF (herein referring to both MRTF-A and MRTF-B), YAP and TAZ (also known as YAP1 and WWTR1, respectively; collectively denoted YAP/TAZ) into the nucleus leads to altered expression of circadian proteins. Simulations from our model predict that lower levels of cytoskeletal activity are associated with longer circadian oscillation periods and higher oscillation amplitudes, which is consistent with recent experimental observations. Furthermore, accumulation of YAP/TAZ and MRTF in the nucleus causes circadian oscillations to decay in our model. These effects hold both at the single-cell level and within a population-level framework. Finally, we investigated the effects of mutations in YAP or lamin A, the latter of which result in a class of diseases known as laminopathies. In silico, oscillations in circadian proteins are substantially weaker in populations of cells with mutations in YAP or lamin A, suggesting that defects in mechanotransduction can disrupt the circadian clock in certain disease states; however, reducing substrate stiffness in the model restores normal oscillatory behavior, suggesting a possible compensatory mechanism. Thus, our study identifies that mechanotransduction could be a potent modulatory cue for cellular clocks and that this crosstalk can be leveraged to rescue the circadian clock in disease states.
Asunto(s)
Relojes Circadianos , Mecanotransducción Celular , Proteínas Señalizadoras YAP , Humanos , Animales , Proteínas Señalizadoras YAP/metabolismo , Simulación por Computador , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Transactivadores/metabolismo , Transactivadores/genética , Modelos Biológicos , Núcleo Celular/metabolismo , Mamíferos/metabolismo , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/metabolismoRESUMEN
Fluid shear stress (FSS) from blood flow, sensed by the vascular endothelial cells (ECs) that line all blood vessels, regulates vascular development during embryogenesis, controls adult vascular physiology and determines the location of atherosclerotic plaque formation. Although a number of papers have reported a crucial role for cell-cell adhesions or adhesion receptors in these processes, a recent publication has challenged this paradigm, presenting evidence that ECs can very rapidly align in fluid flow as single cells without cell-cell contacts. To address this controversy, four independent laboratories assessed EC alignment in fluid flow across a range of EC cell types. These studies demonstrate a strict requirement for cell-cell contact in shear stress sensing over timescales consistent with previous literature and inconsistent with the newly published data.
Asunto(s)
Células Endoteliales , Uniones Intercelulares , Mecanotransducción Celular , Estrés Mecánico , Humanos , Uniones Intercelulares/metabolismo , Células Endoteliales/metabolismo , Animales , Resistencia al Corte , Adhesión Celular/fisiologíaRESUMEN
Biophysical cues have the ability to enhance cellular signaling response to Bone Morphogenetic Proteins, an essential growth factor during bone development and regeneration. Yet, therapeutic application of Bone Morphogenetic Protein 2 (BMP2) is restricted due to uncontrolled side effects. An understanding of the temporal characteristics of mechanically regulated signaling events and underlying mechanism is lacking. Using a 3D bioreactor system in combination with a soft macroporous biomaterial substrate, we mimic the in vivo environment that BMP2 is acting in. We show that the intensity and duration of BMP2 signaling increases with increasing loading frequency in synchrony with the number and size of focal adhesions. Long-term mechanical stimulation increases the expression of BMP receptor type 1B, specific integrin subtypes and integrin clustering. Together, this triggered a short-lived mechanical echo that enhanced BMP2 signaling even when BMP2 is administered directly after mechanical stimulation, but not when it is applied after a resting period of ≥30 min. Interfering with cytoskeletal remodeling hinders focal adhesion remodeling verifying its critical role in shifting cells into a state of high BMP2 responsiveness. The design of biomaterials that exploit this potential locally at the site of injury will help to overcome current limitations of clinical growth factor treatment.
Asunto(s)
Proteína Morfogenética Ósea 2 , Citoesqueleto , Adhesiones Focales , Transducción de Señal , Proteína Morfogenética Ósea 2/metabolismo , Proteína Morfogenética Ósea 2/genética , Adhesiones Focales/metabolismo , Humanos , Citoesqueleto/metabolismo , Mecanotransducción Celular , AnimalesRESUMEN
Mesenchymal stromal cells (MSCs) can be isolated from various tissues of healthy or patient donors to be retransplanted in cell therapies. Because the number of MSCs obtained from biopsies is typically too low for direct clinical application, MSC expansion in cell culture is required. However, ex vivo amplification often reduces the desired MSC regenerative potential and enhances undesired traits, such as activation into fibrogenic myofibroblasts. Transiently activated myofibroblasts restore tissue integrity after organ injury by producing and contracting extracellular matrix into scar tissue. In contrast, persistent myofibroblasts cause excessive scarring-called fibrosis-that destroys organ function. In this review, we focus on the relevance and molecular mechanisms of myofibroblast activation upon contact with stiff cell culture plastic or recipient scar tissue, such as hypertrophic scars of large skin burns. We discuss cell mechanoperception mechanisms such as integrins and stretch-activated channels, mechanotransduction through the contractile actin cytoskeleton, and conversion of mechanical signals into transcriptional programs via mechanosensitive co-transcription factors, such as YAP, TAZ, and MRTF. We further elaborate how prolonged mechanical stress can create persistent myofibroblast memory by direct mechanotransduction to the nucleus that can evoke lasting epigenetic modifications at the DNA level, such as histone methylation and acetylation. We conclude by projecting how cell culture mechanics can be modulated to generate MSCs, which epigenetically protected against myofibroblast activation and transport desired regeneration potential to the recipient tissue environment in clinical therapies.
Asunto(s)
Mecanotransducción Celular , Células Madre Mesenquimatosas , Miofibroblastos , Humanos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Miofibroblastos/metabolismo , Miofibroblastos/citología , Animales , Trasplante de Células Madre Mesenquimatosas/métodos , Regeneración , Diferenciación Celular , Epigénesis GenéticaRESUMEN
Philadelphia-Negative Myeloproliferative neoplasms (MPNs) are a diverse group of blood cancers leading to excessive production of mature blood cells. These chronic diseases, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), can significantly impact patient quality of life and are still incurable in the vast majority of the cases. This review examines the mechanobiology within a bone marrow niche, emphasizing the role of mechanical cues and the primary cilium in the pathophysiology of MPNs. It discusses the influence of extracellular matrix components, cell-cell and cell-matrix interactions, and mechanosensitive structures on hematopoietic stem cell (HSC) behavior and disease progression. Additionally, the potential implications of the primary cilium as a chemo- and mechanosensory organelle in bone marrow cells are explored, highlighting its involvement in signaling pathways crucial for hematopoietic regulation. This review proposes future research directions to better understand the dysregulated bone marrow niche in MPNs and to identify novel therapeutic targets.
Asunto(s)
Cilios , Trastornos Mieloproliferativos , Humanos , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/patología , Trastornos Mieloproliferativos/fisiopatología , Cilios/metabolismo , Cilios/patología , Animales , Médula Ósea/patología , Médula Ósea/metabolismo , Células Madre Hematopoyéticas/metabolismo , Mecanotransducción Celular , Matriz Extracelular/metabolismo , Transducción de Señal , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patologíaRESUMEN
Mechanosensitive ion channel Piezo1 is known to mediate a variety of inflammatory pathways and is also involved in the occurrence and development of many orthopedic diseases. Although its role in the inflammatory mechanism of knee osteoarthritis (KOA) has been reported, a systematic explanation is yet to be seen. This article aims to summarize the role of inflammatory responses in the pathogenesis of KOA and elucidate the mechanism by which the Piezo1-mediated inflammatory response contributes to the pathogenesis of KOA, providing a theoretical basis for the prevention and treatment of knee osteoarthritis. The results indicate that in the mechanism leading to knee osteoarthritis, Piezo1 can mediate the inflammatory response through chondrocytes and synovial cells, participating in the pathological progression of KOA. Piezo1 has the potential to become a new target for the prevention and treatment of this disease. Additionally, as pain is one of the most severe manifestations in KOA patients, the inflammatory response mediated by Piezo1, which causes the release of inflammatory mediators and pro-inflammatory factors leading to pain, can be further explored.
Asunto(s)
Inflamación , Canales Iónicos , Osteoartritis de la Rodilla , Canales Iónicos/metabolismo , Humanos , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/patología , Inflamación/metabolismo , Animales , Condrocitos/metabolismo , Mecanotransducción CelularRESUMEN
Mechanosensitive PIEZO2 ion channels play roles in touch, proprioception, and inflammatory pain. Currently, there are no small molecule inhibitors that selectively inhibit PIEZO2 over PIEZO1. The TMEM120A protein was shown to inhibit PIEZO2 while leaving PIEZO1 unaffected. Here we find that TMEM120A expression elevates cellular levels of phosphatidic acid and lysophosphatidic acid (LPA), aligning with its structural resemblance to lipid-modifying enzymes. Intracellular application of phosphatidic acid or LPA inhibits PIEZO2 but not PIEZO1 activity. Extended extracellular exposure to the non-hydrolyzable phosphatidic acid and LPA analog carbocyclic phosphatidic acid (ccPA) also inhibits PIEZO2. Optogenetic activation of phospholipase D (PLD), a signaling enzyme that generates phosphatidic acid, inhibits PIEZO2 but not PIEZO1. Conversely, inhibiting PLD leads to increased PIEZO2 activity and increased mechanical sensitivity in mice in behavioral experiments. These findings unveil lipid regulators that selectively target PIEZO2 over PIEZO1, and identify the PLD pathway as a regulator of PIEZO2 activity.
Asunto(s)
Canales Iónicos , Lisofosfolípidos , Ácidos Fosfatidicos , Canales Iónicos/metabolismo , Canales Iónicos/genética , Animales , Ácidos Fosfatidicos/metabolismo , Humanos , Ratones , Lisofosfolípidos/metabolismo , Células HEK293 , Fosfolipasa D/metabolismo , Fosfolipasa D/genética , Mecanotransducción Celular , Ratones Endogámicos C57BL , Masculino , OptogenéticaRESUMEN
Vascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS. Smad1/5 limits Akt activation, suggesting that inhibiting Smad1/5 may facilitate outward remodeling. Here we report that high FSS suppresses Smad1/5 by elevating KLF2, which induces the bone morphogenetic protein (BMP) pathway inhibitor, BMP-binding endothelial regulator (BMPER), thereby de-inhibiting Akt. In mice, surgically induced high FSS elevated BMPER expression, inactivated Smad1/5 and induced vessel outward remodeling. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling. Blocking endothelial cell Smad1/5 activation with BMP9/10 blocking antibodies improved vascular remodeling in mouse models of type 1 and type 2 diabetes. Suppression of Smad1/5 is thus a potential therapeutic approach for ischemic disease.
Asunto(s)
Factores de Transcripción de Tipo Kruppel , Proteína Smad1 , Proteína Smad5 , Remodelación Vascular , Animales , Proteína Smad5/metabolismo , Proteína Smad5/genética , Proteína Smad1/metabolismo , Proteína Smad1/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Remodelación Vascular/fisiología , Humanos , Estrés Mecánico , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Masculino , Células Endoteliales/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Ratones Noqueados , Proteínas Proto-Oncogénicas c-akt/metabolismo , Mecanotransducción Celular , Células Cultivadas , Transducción de SeñalRESUMEN
Cell backpacks present significant potential in both therapeutic and diagnostic applications, making it essential to further explore their interactions with host cells. Current evidence indicates that backpacks can induce sustained immune responses. Our original objective was to incorporate a model antigen into the backpacks to promote dendritic cell maturation and facilitate antigen presentation, thereby inducing immune responses. However, we unexpectedly discovered that both antigen-loaded backpacks and empty backpacks demonstrated comparable abilities to induce dendritic cell maturation, resulting in nearly identical potency in T-cell proliferation. Our mechanistic studies suggest that the attachment of backpacks induces mechanical forces on dendritic cells via opening the PIEZO1 mechanical ion channel. This interaction leads to the remodeling of the intracellular cytoskeleton and facilitates the production of type I interferons by dendritic cells. Consequently, the mechano-immune-driven dendritic cell backpacks, when combined with radiotherapy, induce a robust antitumor effect. This research presents an avenue for leveraging mechanotransduction to enhance combination immunotherapeutic strategies, potentially leading to groundbreaking advancements in the field.
Asunto(s)
Células Dendríticas , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Animales , Ratones , Mecanotransducción Celular/inmunología , Ratones Endogámicos C57BL , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/patología , Neoplasias/radioterapia , Proliferación Celular/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Tissue mechanical properties are determined mainly by the extracellular matrix (ECM) and actively maintained by resident cells. Despite its broad importance to biology and medicine, tissue mechanical homeostasis remains poorly understood. To explore cell-mediated control of tissue stiffness, we developed mutations in the mechanosensitive protein talin 1 to alter cellular sensing of ECM. Mutation of a mechanosensitive site between talin 1 rod-domain helix bundles R1 and R2 increased cell spreading and tension exertion on compliant substrates. These mutations promote binding of the ARP2/3 complex subunit ARPC5L, which mediates the change in substrate stiffness sensing. Ascending aortas from mice bearing these mutations showed less fibrillar collagen, reduced axial stiffness, and lower rupture pressure. Together, these results demonstrate that cellular stiffness sensing contributes to ECM mechanics, directly supporting the mechanical homeostasis hypothesis and identifying a mechanosensitive interaction within talin that contributes to this mechanism.