Biology-Basel
·
2024
·Vol. 13
·期 5
·357
·
IF 3.6
Mingxing Ouyang,Qingyu Zhang,Yiming Zhu,Mingzhi Luo,Bing Bu,Linhong Deng
Simple Summaryα-Catenin mediates cell-matrix interactions while Piezo1 at focal adhesions likely mechanosenses traction force through the matrix hydrogel during cell mechanical communication.AbstractCell-to-cell distant mechanical communication has been demonstrated using in vitro and in vivo models. However, the molecular mechanisms underlying long-range cell mechanoresponsive interactions remain to be fully elucidated. This study further examined the roles of α-Catenin and Piezo1 in traction force-induced rapid branch assembly of airway smooth muscle (ASM) cells on a Matrigel hydrogel containing type I collagen. Our findings demonstrated that siRNA-mediated downregulation of α-Catenin or Piezo1 expression or chemical inhibition of Piezo1 activity significantly reduced both directional cell movement and branch assembly. Regarding the role of N-cadherin in regulating branch assembly but not directional migration, our results further confirmed that siRNA-mediated downregulation of α-Catenin expression caused a marked reduction in focal adhesion formation, as assessed by focal Paxillin and Integrin α5 localization. These observations imply that mechanosensitive α-Catenin is involved in both cell–cell and cell-matrix adhesions. Additionally, Piezo1 partially localized in focal adhesions, which was inhibited by siRNA-mediated downregulation of α-Catenin expression. This result provides insights into the Piezo1-mediated mechanosensing of traction force on a hydrogel. Collectively, our findings highlight the significance of α-Catenin in the regulation of cell-matrix interactions and provide a possible interpretation of Piezo1-mediated mechanosensing activity at focal adhesions during cell–cell mechanical communication.
研究领域:
细胞生物学
·
生物力学
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产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Fan Chen,Wenzhe Wang,Zian Zhang,Nanyu Pang,Chang Liu,Zhenchao Huang,Haoshen Wu,Haining Zhang
Osteoarthritis (OA), characterized by progressive cartilage degeneration and chronic joint pain, represents a major global health challenge. While intra-articular drug delivery is a common therapeutic approach, its efficacy is limited by poor drug penetration through the dense cartilage matrix, particularly for hydrophobic compounds. Here, a novel charge-guided micro/nanocarrier system designed to overcome these delivery challenges is presented. By modifying amylose with glycidyl trimethyl ammonium chloride (GTAC), it is developed positively charged carriers that demonstrate enhanced penetration into the negatively charged cartilage matrix. The hydrophobic Piezo1 inhibitor, Margaric acid (MA), is efficiently encapsulated within the helical cavity of modified amylose through DMSO-ultrasound treatment, creating Cationic Amylose Micro/Nanocarriers@MA (CAMNC@MA). This system effectively delivers MA to chondrocytes, where Piezo1, a crucial mechanosensor implicated in OA development, can be precisely modulated. These results demonstrate that CAMNC@MA successfully inhibits abnormal mechanical force-induced Piezo1 activation in chondrocytes, enhances cell survival, reduces matrix degradation, and effectively alleviates OA progression. This innovative drug delivery platform offers a promising strategy for clinical OA treatment by combining enhanced matrix penetration with efficient matrix penetration of hydrophobic therapeutic agents.
研究领域:
医学
·
药理学
·
生物材料学
✓ 已验证
DOI
高影响因子
ULTRASONICS SONOCHEMISTRY
·
2021
·
IF 7.491
Xuelian Shen,Zhuqing Song,Erjiao Xu,Jun Zhou,Fei Yan
Neuromodulation by ultrasound (US) has recently drawn considerable attention due to its great advantages in noninvasiveness, high penetrability across the skull and highly focusable acoustic energy. However, the mechanisms and safety from US irradiation still remain less understood. Recently, documents revealed Piezo1, a mechanosensitive cation channel, plays key role in converting mechanical stimuli from US through its trimeric propeller-like structure. Here, we developed a Piezo1-targeted microbubble (PTMB) which can bind to the extracellular domains of Piezo1 channel. Due to the higher responsiveness of bubbles to mechanical stimuli from US, significantly lower US energy for these PTMB-binding cells may be needed to open these mechanosensitive channels. Our results showed US energy at 0.03 MPa of peak negative pressure can achieve an equivalent level of cytoplasmic Ca 2+ transients which generally needs 0.17 MPa US intensity for the control cells. Cytoplasmic Ca 2+ elevations were greatly reduced by chelating extracellular calcium ions or using the cationic ion channel inhibitors, confirming that US-mediated calcium influx are dependent on the Piezo1 channels. No bubble destruction and obvious temperature increase were observed during the US exposure, indicating cavitation and heating effects hardly participate in the process of Ca 2+ transients. In conclusion, our study provides a novel strategy to sensitize the response of nerve cells to US stimulation, which makes it safer application for US-mediated neuromodulation in the future.
研究领域:
神经科学
·
生物医学工程
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Donghao Gan,Yi Ran,Hong Pan,Qinnan Yan,Wenjing Zhang,Bo Zhou,Pengzhi Xu,Rongdong Liao,Haipeng Xue,Will Jiang,Tailin He,Qingyun Jia,Lei Qin,Francis Y Lee,Di Chen,Chuanju Liu,Guozhi Xiao
The mechanosensitive Piezo1 channel protein plays a pivotal role in promoting bone formation and repair; however, its underlying molecular mechanism(s) are poorly defined. Here this study shows that Sirt1 positively regulates Piezo1 expression and activity to promote osteogenesis and bone repair in mice. This study finds that Piezo1 is up-regulated in the cartilage callus during bone repair. Deleting Piezo1 in chondrocytes largely impairs endochondral ossification and mechanically induced osteogenesis and delays fracture healing in mice, while Yoda1 activation of Piezo1 exerts opposite effects. Sirt1 overexpression or activation dramatically increases Piezo1 protein expression in a dose-dependent manner. Sirt1 binds to Piezo1 protein and deacetylates and activates Piezo1 and Ca 2+ influx in chondrocytes. Piezo1 loss in chondrocytes abolishes the ability of Sirt1 activator SRT2104 to accelerate bone repair. Resveratrol (RSV), a natural Sirt1 activator, also potently activates Piezo1 and enhances bone repair. A yeast microcapsule-based oral formulation of RSV (YC-RSV) is developed to improve drug bioavailability and therapeutic efficacy, which highly and selectively targets to the inflammatory fracture site. Thus, it demonstrates that Sirt1 is a novel and potent activator of Piezo1 to promote bone formation and repair, supporting the potential clinical application of Sirt1 activators in promoting bone formation and repair.
研究领域:
分子生物学
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骨骼生物学
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再生医学
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信号转导
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
·
2025
·
IF 4.3
Fan Yanan,An Caizhelin,Wang Zhihui,Luo Jia,Wang Wenbin,Luo Qing,Song Guanbin
Hepatocytes are the primary functional cells in the liver, and the malignant transformation of hepatocytes significantly contributes to hepatocellular carcinoma (HCC) progression. Liver fibrosis and cirrhosis caused by extracellular matrix (ECM) remodeling during liver lesions is a pivotal driver of HCC. However, the impact of matrix stiffness on hepatocytes and the underlying molecular mechanisms are not fully understood. Herein, using gelatin/sodium alginate hydrogels with different stiffnesses to simulate the change of matrix stiffness during liver lesions, we found that matrix stiffening leads to a notable decrease in the expression of hepatocyte nuclear factor 4α (HNF4α) and functional hepatocyte genes and a significant increase in the expression of interleukin 6 (IL‒6) in human hepatocyte line L‒02 cells, indicating obvious damage of hepatocyte function. In addition, matrix stiffening causes extensive DNA damage to L‒02 cells. Mechanistically, matrix stiffening upregulates piezo‒type mechanosensitive ion channel component 1 (Piezo1) expression and activates extracellular signal‒regulated kinase 1/2 (ERK1/2) signaling. Piezo1 knockdown suppresses matrix stiffening‒induced functional impairment and DNA damage in L‒02 cells. Moreover, Piezo1 knockdown blocks matrix stiffening‒activated ERK1/2 signaling in L‒02 cells. U0126 (a selective inhibitor of ERK1/2 activation) treatment could rescue matrix stiffening‒induced functional impairment and DNA damage. Taken together, these findings demonstrate that matrix stiffening induces functional impairment and DNA damage in L‒02 cells via the Piezo1‒ERK1/2 signaling pathway, which provides evidence for a better understanding of the hepatocyte function damage caused by tissue mechanical microenvironment change in liver diseases and the mechanotransduction in this process. Graphical abstract An increase in matrix stiffness inhibits HNF4α expression and promotes IL‒6 expression in L‒02 cells. Meanwhile, matrix stiffening induces L‒02 cell DNA damage and upregulates the expression of γ‒H2AX and 53BP1. These findings prove that matrix stiffness is a crucial mechanical regulator of cellular functional impairment and DNA damage and plays an important role in liver disease.
研究领域:
医学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Hailin Liu,Lian Zhou,Xifeng Wang,Qingcui Zheng,Fenfang Zhan,Lanqian Zhou,Yao Dong,Yanhong Xiong,Pengcheng Yi,Guohai Xu,Fuzhou Hua
The side effects of high-dose dexamethasone in anti-infection include increased ROS production and immune cell apoptosis. Dexamethasone effectively activates serum/glucocorticoid-regulated kinase 1 (SGK1), which upregulates various ion channels by activating store-operated calcium entry (SOCE), leading to Ca 2+ oscillations. PIEZO1 plays a crucial role in macrophages' immune activity and function, but whether dexamethasone can regulate PIEZO1 by enhancing SOCE via SGK1 activation remains unclear. The effects of dexamethasone were assessed in a mouse model of sepsis, and primary BMDMs and the RAW264.7 were treated with overexpression plasmids, siRNAs, or specific activators or inhibitors to examine the relationships between SGK1, SOCE, and PIEZO1. The functional and phenotypic changes of mouse and macrophage models were detected. The results indicate that high-dose dexamethasone upregulated SGK1 by activating the macrophage glucocorticoid receptor, which enhanced SOCE and subsequently activated PIEZO1. Activation of PIEZO1 resulted in Ca 2+ influx and cytoskeletal remodelling. The increase in intracellular Ca 2+ mediated by PIEZO1 further increased the activation of SGK1 and ORAI1/STIM1, leading to intracellular Ca 2+ peaks. In the context of inflammation, activation of PIEZO1 suppressed the activation of TLR4/NFκB p65 in macrophages. In RAW264.7 cells, PIEZO1 continuous activation inhibited the change in mitochondrial membrane potential, accelerated ROS accumulation, and induced autophagic damage and cell apoptosis in the late stage. CaMK2α was identified as a downstream mediator of TLR4 and PIEZO1, facilitating high-dose dexamethasone-induced macrophage immunosuppression and apoptosis. PIEZO1 is a new glucocorticoid target to regulate macrophage function and activity. This study provides a theoretical basis for the rational use of dexamethasone.
研究领域:
免疫学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Zichen Yang,Yuge Zhao,Xiaoyou Zhang,Li Huang,Kun Wang,Jiuyuan Sun,Nana Chen,Weimin Yin,Shiyu Chen,Hui Zhi,Liangyi Xue,Lulu An,Rongjie Li,Haiqing Dong,Jinfu Xu,Yan Li,Yongyong Li
The mechanical properties of nanoparticles play a crucial role in regulating nanobiointeractions, influencing processes such as blood circulation, tumor accumulation/penetration, and internalization into cancer cells. Consequently, they have a significant impact on drug delivery and therapeutic efficacy. However, it remains unclear whether and how macrophages alter their biological function in response to nanoparticle elasticity. Here, we report on the nano-mechanical biological effects resulting from the interactions between elastic silica nanoparticles (SNs) and macrophages. The SNs with variational elasticity Young’s moduli ranging from 81 to 837 MPa were synthesized, and it was demonstrated that M2 [tumor-associated macrophages (TAMs)] could be repolarized to M1 by the soft SNs. Additionally, our findings revealed that cell endocytosis, membrane tension, the curvature protein Baiap2, and the cytoskeleton were all influenced by the elasticity of SNs. Moreover, the mechanically sensitive protein Piezo1 on the cell membrane was activated, leading to calcium ion influx, activation of the NF-κB pathway, and the initiation of an inflammatory response. In vivo experiments demonstrated that the softest 81 MPa SNs enhanced tumor penetration and accumulation and repolarized TAMs in intratumoral hypoxic regions, ultimately resulting in a significant inhibition of tumor growth. Taken together, this study has established a cellular feedback mechanism in response to nanoparticle elasticity, which induces plasma membrane deformation and subsequent activation of mechanosensitive signals. This provides a distinctive “nano-mechanical immunoengineering” strategy for reprogramming TAMs to enhance cancer immunotherapy.
研究领域:
纳米技术
·
免疫学
·
生物医学工程
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL NEUROLOGY
·
2024
·
IF 4.6
Tingwang Guo,Gang Chen,Lin Yang,Jia Deng,Yun Pan
In intracerebral hemorrhage (ICH), the mechanical brain injury is a considerable and indispensable factor determining the neurological functions and poor outcomes. Previous studies indicate the mechanically gated ion channel-Piezo1 can transduce mechanical effects following ICH. Isoquercitrin (ISQ) is a well-studied ion channel inhibitor. Furthermore, whether the following Piezo1-mediated neurological impairment can be ameliorated by ISQ remains unclear. Herein, we constructed the hydrostatic pressure model and ICH rat model. Firstly, we found that Piezo1 agonists Yoda1 and Jedi1 facilitated extracellular calcium influx dramatically, but ISQ could depress intracellular Ca 2+ overload under hydrostatic pressure in primary neurons. Then we detected the expression profile of Piezo1, NLRP3 and NF-κB p-p65 after ICH, and found that the expression of Piezo1 was much earlier than NLRP3 and NF-κB p-p65. Furthermore, by western blot and immunofluorescence, ISQ decreased the expression of Piezo1 and NLRP3 dramatically like GsMTx4, but Nigericin as a NLRP3 agonist failed to affect Piezo1. Besides, both ISQ and interfering Piezo1 suppressed the upregulated caspase-1, NF-κB p-p65, p-IκBα, Tunel-positive cells and inflammatory factors (IL-1β, IL-6 and TNF-α) in ICH. At last, the hydrostatic pressure or hematoma induced disturbed neural viability, disordered neural cytomorphology, and increased neurobehavioral and cognitive deficits, but they were improved by ISQ and GsMTx4 strongly. Therefore, ISQ could alleviate neurological injuries induced by Piezo1 via NLRP3 pathway. These observations indicated that Piezos might be the new therapeutic targets, and blocking Piezos/NLRP3 pathway by ISQ could be an auspicious strategy for the treatment of ICH.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEURON
·
2022
·
IF 18.688
Jin Hu,Qiang Chen,Hongrui Zhu,Lichao Hou,Wei Liu,Qihua Yang,Huidan Shen,Guolin Chai,Boxin Zhang,Shaoxuan Chen,Zhiyu Cai,Chongxin Wu,Fan Hong,Hongda Li,Sifang Chen,Naian Xiao,Zhan-xiang Wang,Xueqin Zhang,Bo Wang,Liang Zhang,Wei Mo
Summary The pathology of Alzheimer’s disease (AD) is featured with extracellular amyloid-β (Aβ) plaques, whose impact on the mechanical properties of the surrounding brain tissues is unclear. Microglia sense and integrate biochemical cues of the microenvironment. However, whether the microglial mechanosensing pathways influence AD pathogenesis is unknown. Here, we surveyed the elevated stiffness of Aβ-plaque-associated tissues and observed the selective upregulation of the mechanosensitive ion channel Piezo1 in Aβ-plaque-associated microglia. Piezo1 sensed the stiffness stimuli of Aβ fibrils and subsequently induced Ca 2+ influx for microglial clustering, phagocytosis , and compacting of Aβ plaques. Microglia lacking Piezo1 led to the exacerbation of Aβ pathology and cognitive decline, whereas pharmacological activation of microglial Piezo1 ameliorated brain Aβ burden and cognitive impairment in 5 × FAD mice. Together, our results reveal that Piezo1, a mechanosensor of Aβ fibril stiffness in microglia, represents a potential therapeutic target for AD.
研究领域:
神经科学
·
病理学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2024
·
IF 3.5
Zhao Jiani,Xiong Yacheng,Liu Yu,Ling Jin,Liu Shuai,Wang Wei
Previous large-scale genetic studies have prioritized the causal genes piezo type mechanosensitive ion channel component 1 ( PIEZO1 ) and castor zinc finger 1 ( CASZ1 ) associated with varicose veins (VVs). This study aims to evaluate their roles in both clinical and experimental VVs. In this study, we investigated abundance of PIEZO1 and CASZ1 in both varicose and normal veins from the same patients. Yoda1 (a selective PIEZO1 agonist, 2.6 mg/kg/day) or vehicle was administered intraperitoneally for 3 weeks to evaluate the effect of PIEZO1 activation on experimental VVs. Subsequently, endothelial Piezo1 deletion mice ( Piezo1 iΔEC mice) were generated to explored the role of endothelial PIEZO1 on VVs. Laser speckle imaging, flow cytometry, cell tracing with Evans blue or rhodamine-6G, and histopathological staining were utilized to evaluate the pathophysiology of VVs. Our results showed that mRNA expression of PIEZO1 , but not CASZ1 , was abundant and increased in clinical VVs. The Piezo1 tP1−td mice revealed endothelium-specific expression of PIEZO1 in mice veins. By establishing iliac vein ligation-induced VVs in mice, Yoda1 exacerbated experimental VVs with increased inflammatory cell infiltration. Subsequently, endothelial Piezo1 deletion ( Piezo1 iΔEC mice) alleviated experimental VVs and vascular remodeling by directly reducing vascular permeability and leukocyte-endothelium interactions compared to the control ( Piezo1 fl/fl mice). PIEZO1 is highly expressed in clinical VVs, meanwhile, activation or inhibition of PIEZO1 exerts a remarkable effect on experimental VVs. Furthermore, Piezo1 may constitute a potential therapeutic approach for the medical treatment of VVs.
研究领域:
心血管疾病
·
分子生物学
·
实验病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2025
·Vol. 10
·期 1
·1-19
·
IF 52.7
Wang Baile,Liu Jie,Wang Qin,Arhatte Malika,Cheong Lai Yee,Glogowska Edyta,Jiang Xue,Chung Sookja Kim,Jin Leigang,Hu Qianxing,Wang Yu,Honoré Eric,Xu Aimin
With aging or osteoporosis, bone marrow adipogenesis is increased and inversely correlates with the loss of bone mass. Bone marrow adipocytes are derived from multipotent bone marrow mesenchymal stem cells (BMMSCs), which can differentiate into either fat or bone. BMMSCs are mechanosensitive cells, but how mechanical loading is implicated in the in vivo regulation of bone marrow adipogenesis and its impact on bone remodeling remain poorly understood. Here, we identify the mechanosensitive cationic channel Piezo1 in BMMSCs as a key suppressor of bone marrow adipogenesis by preventing local inflammation, thereby enhancing osteoblast differentiation and bone formation. Mice with a specific Piezo1 invalidation in BMMSCs exhibit osteoporosis and marrow adiposity, together with resistance to the beneficial effects of exercise on bone health. Accordingly, Piezo1-deficient BMMSCs in vitro preferentially differentiate into adipocytes rather than osteoblasts. Invalidation of Piezo1 in BMMSCs enhances the autocrine activation of CCR2 by Ccl2, which further induces lipocalin-2 (Lcn2) production via NF-κB activation, thereby promoting adipocyte differentiation. Conversely, Piezo1 opening induces Klf2 expression through CaMKII, preventing c-Jun activation, Ccl2 production and bone marrow adipogenesis. These findings demonstrate that Piezo1 activation in BMMSCs suppresses bone marrow adipogenesis to maintain bone strength by preventing the Ccl2-Lcn2 inflammatory autocrine loop, thus uncovering a previously unrecognized link between mechanotransduction, inflammation, and cell fate determination.
研究领域:
骨生物学
·
干细胞生物学
·
机械转导
·
炎症与免疫
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代谢性骨病
·
分子细胞生物学
·
转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-20
·
IF 12.6
Yang Jinghong,Li Runli,Wang Xiaoshuang,Lu Dongheng,Li Weichang,Wang Yan
Irregular alveolar bone defects pose persistent clinical challenges due to their complex morphology and the lack of biomaterials that simultaneously provide structural integrity, biocompatibility, and dynamic osteoinductive potential. Herein, we report a fiber-reinforced, dual-network hydrogel system (OHADN fiber@Yoda1 hydrogel) engineered to recapitulate mechanobiological cues for enhanced bone regeneration. This injectable hydrogel integrates oxidized hyaluronic acid (OHA) crosslinked with Yoda1-loaded PLGA-collagen fiber fragments and stabilized via catechol-Fe³⁺ coordination, forming a robust and self-healing structure. The fiber network enhances matrix stiffness and sustains Yoda1 release, promoting PIEZO1 activation in stem cells and enabling persistent mechanotransduction. In vitro, this system effectively regulates macrophage polarization, maintains cellular tension homeostasis, and significantly upregulates osteogenic markers via the PIEZO1–ITGα5 axis. Transcriptomic profiling and mechanistic validation revealed that focal adhesion and cytoskeletal signaling pathways are enriched upon hydrogel treatment. In a rat alveolar bone defect model, the OHADN fiber@Yoda1 hydrogel demonstrated superior bone volume restoration and trabecular architecture compared to conventional materials. This work presents a promising paradigm for spatiotemporal control of osteoimmune microenvironments through mechanoresponsive biomaterials.Graphical abstract
研究领域:
生物材料
·
组织工程
·
机械生物学
·
再生医学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）