Introduction Excessive narrowing of airways is the most important pathological feature of asthma,but its mechanism remains puzzling.One certain thing is that the contraction of airway smooth muscle(ASM)ultimately caus...Introduction Excessive narrowing of airways is the most important pathological feature of asthma,but its mechanism remains puzzling.One certain thing is that the contraction of airway smooth muscle(ASM)ultimately causes airway narrowing,thus both structural and functional alterations of airway smooth muscle(ASM)are thought as common final pathway responsible for the bronchial hyperresponsiveness(BHR),the hall mark of asthma.Many chemical and physical factors such as air pollutants,inflammatory agents,mechanical and geometrical properties of the microenvironment could influence structure and/or function of ASM cells.In addition,some re-展开更多
Introduction A disintegrin and metalloproteinase 33（ADAM33）has been identified as a susceptibility gene for asthma<sup>[1]</sup>,In particular,ADAM33 mRNA is highly expressed in airway smooth muscle cell...Introduction A disintegrin and metalloproteinase 33（ADAM33）has been identified as a susceptibility gene for asthma<sup>[1]</sup>,In particular,ADAM33 mRNA is highly expressed in airway smooth muscle cells（ASMCs）and the level of soluble ADAM33（sADAM33）is known to inversely correlate with lung function such as bronchial hyperresponsiveness（BHR）<sup>[2]</sup>that is ultimately determined by the mechanical behaviors of ASMCs.However,few have studied how sADAM33would affect ASMC mechanics.Here,we manipulated the expression of SADAM33 in展开更多
In this study,we hypothesized that Piezo 1 channels mediate the compression-enhanced invasive phenotype of cancer cells via a caveolae-dependent mechanism.To test this hypothesis,we examined in vitro cultured human br...In this study,we hypothesized that Piezo 1 channels mediate the compression-enhanced invasive phenotype of cancer cells via a caveolae-dependent mechanism.To test this hypothesis,we examined in vitro cultured human breast cancer cells for their ability to invade and degrade extracellular matrix in the presence or absence of compressive stress,together with corresponding changes in Piezo1 as well as cytoskeletal remodeling and calcium signaling.Here we show that compressive stress enhanced invasion,matrix degradation,and invadopodia formation of breast cancer cells.We further identified Piezo1 as the putative mechanosensitive cellular component that transmits compression to induce calcium influx,which in turn triggers several downstream pathways.Interestingly,for the first time we observed inv-adopodia with matrix degradation ability on the apical side of the cells, similar to those commonly observed at the cell s ventral side.Furthermore,we demonstrate that Piezo1 and caveolae were both involved in mediating the compressive stress-induced cancer cell invasive phenotype as Piezo 1 and caveolae were often colocalized,and reduction of Cav-1 expression or disruption of caveolae with methyl-β-cyclodextrin led to not only reduced Piezo1 expression but also attenuation of the invasive phenotypes promoted by compressive stress.Taken together,we first observed that in breast cancer cells,simulating uncontrolled growth-induced compressive stress enhanced cancer cell invasion,matrix degradation,and invadopodia and stress fiber formation.Our study also confirmed that Piezo1 channels are highly expressed in breast cancer cells compared to normal breast cells,and is consistent with the data that compressive stress regulates cell migration of breast cancer cells but not normal breast cells.Additionally,we identified that Piezol mediated these processes and the invasive phenotypes also depended on the integrity of caveolae.These findings provide the first demonstration that compressive stress enhances matrix degradation by breast cancer cells and Piezo1 is an essential mechanosensor and transducer for such stress in breast cancer.Additionally,our data supports the model where caveolae might be the'mechanical force foci'which concentrates Piezol to facilitate force sensing and transduction in mammalian cells.Our work may have relevance to human tumors in vivo.As solid tumor experiences high compressive stress due to uncontrolled proliferation and confinement by the stiff extracellular matrix environment,this microenvironment facilitates compression-enhanced cell invasion.The identification of Piezo1’s crucial role in this process provides the first demonstration of the dependence of Piezo1 channels on the response of breast cancer cells to physiological compressive stress.The functional dependence of Piezo1 on caveolae further highlights the importance of membrane organization and composition on forcegated ion channels.Both of these findings underscore the cardinal role that Piezo1 channels play in regulating cell invasion and may inspire further development targeting Piezol as a potential cancer therapeutic target.展开更多
Targeted peptides have been identified as showing great promise for treatment of various diseases including asthma.Asthma is considered of difficuIt-to-treat due to its unclear etiology,thus usually requiring life-lon...Targeted peptides have been identified as showing great promise for treatment of various diseases including asthma.Asthma is considered of difficuIt-to-treat due to its unclear etiology,thus usually requiring life-long treatment.Current strategies for asthma therapy are hampered with undesirable side effects,poor targeting and failure in modulating airway hyperresponsiveness,leading to pressing need of developing more targeted and effective therapeutic sites for asthma.Recently,a disintegrin and metalloproteinase 8(ADAM8)have been shown to over-展开更多
Mechanobiology has been a highly recognized field in studying the importance of physical forces in physiologies at the molecular,cellular,tissue,organ and body-levels.Beside the intensive work focusing on the fine loc...Mechanobiology has been a highly recognized field in studying the importance of physical forces in physiologies at the molecular,cellular,tissue,organ and body-levels.Beside the intensive work focusing on the fine local biomechanical forces,the long-range force which can propagate through a relatively distant scale(in hundreds of micrometers and beyond)has been an intriguing topic with increasing attentions in recent years.The collective functions at cell population level often rely on cell-cell communications with or without direct contacts.Recent progresses including our own work indicate that the long-range biomechanical force propagating across scales far beyond single cell size may reserve the capability to trigger coordinative biological responses within cell population.Whether and how cells communicate mechanically in a distant manner remains largely to be explored.In respiratory system,the mechanical property of airway smooth muscle(ASM)is associated with asthma attack with prolonged contraction during airway hyper-responsiveness.In this work,we found that ASM cells rapidly self-assembled into a well-constructed network on 3D matrigel containing type I collagen(COL I),which required the collective functions and coordination of thousands of cells completed within 12-16 hours.Cells were assembled with aligned actin stress fibers and elongated nuclei.The assembling process relied on the long-range mechanical forces across the matrix to direct cell-cell distant interactions.We further found that single ASM cells could rapidly initiate multiple buds precisely pointing to neighboring cells in distance,which relied on cell traction force and force strain on the matrix.Beads tracking assay demonstrated the long-range transmission of cellular traction force to distant locations,and modeling of maximum strain distribution on matrix by finite element method predicted the consistency with cell directional protrusions and movements in experiments.Cells could sense each other in distance to move directionally on both non-fibrous matrigel and in much more efficient way when containing COL I.Cells recruited COL I from the hydrogel to build nearly identical COL I fibrous network to mechanically stabilize the cell network.Our results revealed that ASM cells can sense the traction strain transmitted through matrix to initiate distant communications and rapidly coordinate the network assembly at the population level through active cell-matrix interactions.As an interesting phenomenon,cells sound able to’make phone call’via the role of long-range mechanical force.In summary,this work demonstrated that long-range biomechanical force facilitates the collective functions of ASM cell population for network assembly.The cells reacted to traction strain on the matrix for distant communications,which resulted in directional budding and movement.Fibrous COL I had important roles in facilitating the efficiency of force transmission to induce the assembly and stabilizing the cell network.This work has helped advance the understanding of the feature andfunction of long-range biomechanical force at the cell population level.The observed high mechano-sensitivity of ASM cells might suggest a re-enforced feedback of enhanced contraction by excessive ASM under asthmatic condition.展开更多
Smooth muscle cells can work properly over a large length range,drastic reorganization of the cytoskeletal structure has to occur,but the mechanism behind the process of cytoskeleton reorganization of smooth muscle is...Smooth muscle cells can work properly over a large length range,drastic reorganization of the cytoskeletal structure has to occur,but the mechanism behind the process of cytoskeleton reorganization of smooth muscle is still poorly understood,especially with respect to unique problem of maintaining force generation and transmission within the confine of an ever-changing cytoskeleton in smooth muscle.Using a cytoskeletal preparation derived from skinned airway smooth muscle,we aimed at separating the contribution of actomyosin interaction and elucidating the cytoskeletal stiffness in smooth muscle.The results indicate that there is a Ca++de-展开更多
基金supported by National Natural Science Foundation of China(Grant No. 11172340)Training Program for Hundreds of Distinguished Leading Scientists of Chongqing+3 种基金Chongqing Natural Science Foundation(Grant No.CSTC2010BA5001,CSTC2012jjA0588)Fundamental Research Funds for the Central Universities(Grant No.CQDXWL-2012-123)Specialized Research Fund for the Doctoral Program of Higher Education of China(Grant No.20120191120032)Sharing Fund of Chongqing University's LargeScale Equipment(Grant No.2010063057,2011063048,2011063049)
文摘Introduction Excessive narrowing of airways is the most important pathological feature of asthma,but its mechanism remains puzzling.One certain thing is that the contraction of airway smooth muscle(ASM)ultimately causes airway narrowing,thus both structural and functional alterations of airway smooth muscle(ASM)are thought as common final pathway responsible for the bronchial hyperresponsiveness(BHR),the hall mark of asthma.Many chemical and physical factors such as air pollutants,inflammatory agents,mechanical and geometrical properties of the microenvironment could influence structure and/or function of ASM cells.In addition,some re-
基金supported by National Natural Science Foundation of China(11172340)Training Program for Hundreds of Distinguished Leading Scientists of ChongqingSpecialized Research Fund for the Doctoral Program of Higher Education of China(20120191120032)
文摘Introduction A disintegrin and metalloproteinase 33（ADAM33）has been identified as a susceptibility gene for asthma<sup>[1]</sup>,In particular,ADAM33 mRNA is highly expressed in airway smooth muscle cells（ASMCs）and the level of soluble ADAM33（sADAM33）is known to inversely correlate with lung function such as bronchial hyperresponsiveness（BHR）<sup>[2]</sup>that is ultimately determined by the mechanical behaviors of ASMCs.However,few have studied how sADAM33would affect ASMC mechanics.Here,we manipulated the expression of SADAM33 in
基金supported by Key Program of NSF of China ( 11532003) to L.D.NSF-MCB 1561794 to A.P.L.
文摘In this study,we hypothesized that Piezo 1 channels mediate the compression-enhanced invasive phenotype of cancer cells via a caveolae-dependent mechanism.To test this hypothesis,we examined in vitro cultured human breast cancer cells for their ability to invade and degrade extracellular matrix in the presence or absence of compressive stress,together with corresponding changes in Piezo1 as well as cytoskeletal remodeling and calcium signaling.Here we show that compressive stress enhanced invasion,matrix degradation,and invadopodia formation of breast cancer cells.We further identified Piezo1 as the putative mechanosensitive cellular component that transmits compression to induce calcium influx,which in turn triggers several downstream pathways.Interestingly,for the first time we observed inv-adopodia with matrix degradation ability on the apical side of the cells, similar to those commonly observed at the cell s ventral side.Furthermore,we demonstrate that Piezo1 and caveolae were both involved in mediating the compressive stress-induced cancer cell invasive phenotype as Piezo 1 and caveolae were often colocalized,and reduction of Cav-1 expression or disruption of caveolae with methyl-β-cyclodextrin led to not only reduced Piezo1 expression but also attenuation of the invasive phenotypes promoted by compressive stress.Taken together,we first observed that in breast cancer cells,simulating uncontrolled growth-induced compressive stress enhanced cancer cell invasion,matrix degradation,and invadopodia and stress fiber formation.Our study also confirmed that Piezo1 channels are highly expressed in breast cancer cells compared to normal breast cells,and is consistent with the data that compressive stress regulates cell migration of breast cancer cells but not normal breast cells.Additionally,we identified that Piezol mediated these processes and the invasive phenotypes also depended on the integrity of caveolae.These findings provide the first demonstration that compressive stress enhances matrix degradation by breast cancer cells and Piezo1 is an essential mechanosensor and transducer for such stress in breast cancer.Additionally,our data supports the model where caveolae might be the'mechanical force foci'which concentrates Piezol to facilitate force sensing and transduction in mammalian cells.Our work may have relevance to human tumors in vivo.As solid tumor experiences high compressive stress due to uncontrolled proliferation and confinement by the stiff extracellular matrix environment,this microenvironment facilitates compression-enhanced cell invasion.The identification of Piezo1’s crucial role in this process provides the first demonstration of the dependence of Piezo1 channels on the response of breast cancer cells to physiological compressive stress.The functional dependence of Piezo1 on caveolae further highlights the importance of membrane organization and composition on forcegated ion channels.Both of these findings underscore the cardinal role that Piezo1 channels play in regulating cell invasion and may inspire further development targeting Piezol as a potential cancer therapeutic target.
基金supported by National Natural Science Foundation of China(11172340)Training Program for Hundreds of Distinguished Leading Scientists of Chongqing,Specialized Research Fund for the Doctoral Program of Higher Education of China(20120191120032)
文摘Targeted peptides have been identified as showing great promise for treatment of various diseases including asthma.Asthma is considered of difficuIt-to-treat due to its unclear etiology,thus usually requiring life-long treatment.Current strategies for asthma therapy are hampered with undesirable side effects,poor targeting and failure in modulating airway hyperresponsiveness,leading to pressing need of developing more targeted and effective therapeutic sites for asthma.Recently,a disintegrin and metalloproteinase 8(ADAM8)have been shown to over-
基金supported financially by Natural Science Foundation of China ( 11532003,11872129, 31670950)Natural Science Foundation of Jiangsu Province ( BK20181416)CZSTB Grant ( CZ20180017) from Changzhou City,Jiangsu Province
文摘Mechanobiology has been a highly recognized field in studying the importance of physical forces in physiologies at the molecular,cellular,tissue,organ and body-levels.Beside the intensive work focusing on the fine local biomechanical forces,the long-range force which can propagate through a relatively distant scale(in hundreds of micrometers and beyond)has been an intriguing topic with increasing attentions in recent years.The collective functions at cell population level often rely on cell-cell communications with or without direct contacts.Recent progresses including our own work indicate that the long-range biomechanical force propagating across scales far beyond single cell size may reserve the capability to trigger coordinative biological responses within cell population.Whether and how cells communicate mechanically in a distant manner remains largely to be explored.In respiratory system,the mechanical property of airway smooth muscle(ASM)is associated with asthma attack with prolonged contraction during airway hyper-responsiveness.In this work,we found that ASM cells rapidly self-assembled into a well-constructed network on 3D matrigel containing type I collagen(COL I),which required the collective functions and coordination of thousands of cells completed within 12-16 hours.Cells were assembled with aligned actin stress fibers and elongated nuclei.The assembling process relied on the long-range mechanical forces across the matrix to direct cell-cell distant interactions.We further found that single ASM cells could rapidly initiate multiple buds precisely pointing to neighboring cells in distance,which relied on cell traction force and force strain on the matrix.Beads tracking assay demonstrated the long-range transmission of cellular traction force to distant locations,and modeling of maximum strain distribution on matrix by finite element method predicted the consistency with cell directional protrusions and movements in experiments.Cells could sense each other in distance to move directionally on both non-fibrous matrigel and in much more efficient way when containing COL I.Cells recruited COL I from the hydrogel to build nearly identical COL I fibrous network to mechanically stabilize the cell network.Our results revealed that ASM cells can sense the traction strain transmitted through matrix to initiate distant communications and rapidly coordinate the network assembly at the population level through active cell-matrix interactions.As an interesting phenomenon,cells sound able to’make phone call’via the role of long-range mechanical force.In summary,this work demonstrated that long-range biomechanical force facilitates the collective functions of ASM cell population for network assembly.The cells reacted to traction strain on the matrix for distant communications,which resulted in directional budding and movement.Fibrous COL I had important roles in facilitating the efficiency of force transmission to induce the assembly and stabilizing the cell network.This work has helped advance the understanding of the feature andfunction of long-range biomechanical force at the cell population level.The observed high mechano-sensitivity of ASM cells might suggest a re-enforced feedback of enhanced contraction by excessive ASM under asthmatic condition.
基金supported by National Natural Science Foundation of China(11172340)Training Program for Hundreds of Distinguished Leading Scientists of ChongqingSpecialized Research Fund for the Doctoral Program of Higher Education of China(20120191120032)
文摘Smooth muscle cells can work properly over a large length range,drastic reorganization of the cytoskeletal structure has to occur,but the mechanism behind the process of cytoskeleton reorganization of smooth muscle is still poorly understood,especially with respect to unique problem of maintaining force generation and transmission within the confine of an ever-changing cytoskeleton in smooth muscle.Using a cytoskeletal preparation derived from skinned airway smooth muscle,we aimed at separating the contribution of actomyosin interaction and elucidating the cytoskeletal stiffness in smooth muscle.The results indicate that there is a Ca++de-
