Receptor-ligand interactions in blood flow are crucial to initiate such biological processes as inflammatory cascade,platelet thrombosis,as well as tumor metastasis.To mediate cell adhesion,the interacting receptors a...Receptor-ligand interactions in blood flow are crucial to initiate such biological processes as inflammatory cascade,platelet thrombosis,as well as tumor metastasis.To mediate cell adhesion,the interacting receptors and ligands must be anchored onto two apposing surfaces of two cells or a cell and a substratum,i.e.,two-dimensional（2D）binding,which is different from the binding of a soluble ligand in fluid phase to a receptor,i.e.,three-dimensional（3D） binding.While numerous works have been focused on3 D kinetics of receptor-ligand interactions in the immune system,2D kinetics and its regulations have been less understood,since no theoretical framework or experimental assays were established until 1993.Not only does the molecular structure dominate 2D binding kinetics,but the shear force in blood flow also regulates cell adhesion mediated by interacting receptors and ligands.Here,we provide an overview of current progress in 2D binding and regulations,mainly from our group.Relevant issues of theoretical frameworks,experimental measurements,kinetic rates and binding affinities,and force regulations are discussed.展开更多
Blood flow inside the liver plays a key role in hepatic functions, and abnormal hemodynamics are highly correlated with liver diseases. To date, the flow field in an elementary building block of the organ, the liver l...Blood flow inside the liver plays a key role in hepatic functions, and abnormal hemodynamics are highly correlated with liver diseases. To date, the flow field in an elementary building block of the organ, the liver lobule,is difficult to determine experimentally in humans due to its complicated structure, with radially branched microvasculature and the technical difficulties that derive from its geometric constraints. Here we established a set of 3D computational models for a liver lobule using porous media theory and analyzed its flow dynamics in normal, fibrotic,and cirrhotic lobules. Our simulations indicated that those approximations of ordinary flow in portal tracts（PTs） and the central vein, and of porous media flow in the sinusoidal network, were reasonable only for normal or fibrotic lobules.Models modified with high resistance in PTs and collateral vessels inside sinusoids were able to describe the flow features in cirrhotic lobules. Pressures, average velocities, and volume flow rates were profiled and the predictions compared well with experimental data. This study furthered our understanding of the flow dynamics features of liver lobules and the differences among normal, fibrotic, and cirrhotic lobules.展开更多
Blood cell aggregation and adhesion to endothelial cells under shear flow are crucial to many biological processes such as thrombi formation, inflammatory cascade, and tumor metastasis, in which these cellular interac...Blood cell aggregation and adhesion to endothelial cells under shear flow are crucial to many biological processes such as thrombi formation, inflammatory cascade, and tumor metastasis, in which these cellular interactions are mainly mediated by the underlying receptor-ligand bindings. While theoretical modeling of aggregation dynamics and adhesion kinetics of interacting cells have been well studied separately, how to couple these two processes remains unclear. Here we develop a combined model that couples cellular aggregation dynamics and adhesion kinetics under shear flow. The impacts of shear rate （or shear stress） and molecular binding affinity were elucidated. This study provides a unified model where the action of a fluid flow drives cell aggregation and adhesion under the modulations of the mechanical shear flow and receptor-ligand interaction kinetics. It offers an insight into understanding the relevant biological processes and functions.展开更多
Atherosclerosis or fibrosis and cirrhosis undergo chronic inflammation associated with the adhesion between neutrophils and endothelial cells(ECs)that is mediated by their respective cellular adhesive molecules on sti...Atherosclerosis or fibrosis and cirrhosis undergo chronic inflammation associated with the adhesion between neutrophils and endothelial cells(ECs)that is mediated by their respective cellular adhesive molecules on stiffened blood vessel wall or extracellular matrix(ECM)under shear flow[1-3].However,the mechanical dependence of calcium flux and trail formation in neutrophils remains unclear yet in these processes.First,the effect of substrate stiffness through ECs on neutrophil calcium spike was quantified when the individual neutrophils adhered to EC monolayer pre-placed onto stiffness-varied polyacrylamide(PA)substrate(5 or 34.88 kPa)or glass surface.Our data indicated that E-/P-selectins and ICAM-1s on HUVECs and b2-integrins,PSGL-1s,and CD44s on neutrophils were all involved in mediating neutrophil calcium spike in a stiffness-dependent manner,in which the increase of substrate stiffness enhanced the calcium intensity and spike number.Such stiffness-dependent calcium response is associated with selectin-induced b2-integrin activation through Syk/Src signaling pathway and the F-actin/myosin II function.Moreover,tension-activated calcium ion channels displayed critical roles in initiating stiffness-dependent calcium spike [4].Second,the trail formation of neutrophils to ECs monolayer pre-placed onto the same PA substrate were also tested under shear flow.Live fluorescence imaging showed that neutrophils are able to form long membrane tethers during migration and subsequently leave behind membranous long-lasting trails under shear,which are enriched in LFA-1,Mac-1,and CD44.Moreover,the formation of the trails was inhibited by blocking LFA-1s and Mac-1s,suggesting an important role forβ2-integrins in the trial formation.The recruitment of monocytes was inhibited when pre-blocking ICAM-1s on flowing monocytes,indicating that the neutrophil’s trails employβ2-integrin-ICAM-1 binding to recruit the monocytes.Intriguingly,both the length and the area of the trails increase with increasing substrate stiffness,resulting in the enhanced monocyte recruitment.Inhibition of actin binding protein Arp2/3 impairs the trail formation and dramatically decreases the neutrophil-dependent monocyte recruitment.These data provide an insight into understanding how stiffening of vascular wall could regulate the calcium flux of adhered neutrophils and thus the immune responses in atherosclerosis.They also imply that local mechanical microenvironment is remodeled with the migration of neutrophils,leaving the trails presented to induce and regulate monocyte recruitment.All the results are meaningful in elucidating the occurrence and development of atherosclerosis or fibrosis from the viewpoint of mechanotransduction and also for the potential intervention of cardiovascular disease progress.展开更多
Neutrophil(PMN)accumulation on liver sinusoidal endothelial cells(LSECs)is crucial to pathogen clearance and tissue damage in the liver sinusoids and controlled by a series of adhesion molecules expressed on the surfa...Neutrophil(PMN)accumulation on liver sinusoidal endothelial cells(LSECs)is crucial to pathogen clearance and tissue damage in the liver sinusoids and controlled by a series of adhesion molecules expressed on the surface of PMNs and LSECs.The role of lymphocyte function-associated antigen-1(LFA-1)and macrophage-1 antigen(Mac-1)in this process is still contentious.Here we compared the dynamic force spectra of the binding ofβ2 integrin to intercellular adhesion molecule-1(ICAM-1)on LSECs using atomic force microscopy(AFM)and performed free and steered molecular dynamics(MD)simulations to analyze their structural bases of LFA-1-or Mac-1-I-domain and ICAM-1-D1 or D3 pair in their force spectra.Our AFM data suggest that the mechanical strength of LFA-1-ICAM-1 bond is significantly stronger than that of Mac-1-ICAM-1 bond,implying a dominate role for LFA-1 to mediate PMN adhesion under shear flow.MD simulations indicated that spontaneous dissociation of Mac-1-I-domain vs.ICAMD3-domain is slower with the stronger interaction energy than that for LFA-1 I-domain vs.ICAM-D1-domain and that the rupture force for Mac-1 is lower than that for LFA-1,which are in qualitative agreement with the above experimental observations.These data indicate that the biomechanical features of LFA-1 and Mac-1 to mediate PMN adhesion on LSECs in vitro are similar with those in other tissues like cerebrovascular endothelium,while Mac-1-mediated PMN recruitment in liver sinusoids may stem from the slow blood flow in vivo.These findings further the understandings of PMN recruitment under shear flow in liver sinusoids.展开更多
Membrane fusion is an important process by which biological membranes perform their life activities. Simulations show that the membrane fusion process happens mainly through three pathways, where the Stalk-Pore hypoth...Membrane fusion is an important process by which biological membranes perform their life activities. Simulations show that the membrane fusion process happens mainly through three pathways, where the Stalk-Pore hypothesis, in which two membranes come into close contact to form a stalk to a hemifusion intermediate, and then the fusion pore opens to achieve completely fusion, is widely accepted, and there exist two free energy barriers that break the current structural steady state for lipid rearrangement. Factors of lipid composition, mechanical environment, protein and ion have regulatory roles in the membrane fusion process by effecting membrane curvature structurally and the free energy barriers from energetic perspective. Meanwhile, many theoretical models, represented by the Helfrich model, have been proposed to predict the membrane fusion process. In this paper, we review the research process of membrane fusion and mainly introduce the dynamics of membrane fusion, regulation factors and typical theoretical models.展开更多
基金supported by Natural Science Foundation of China(grants 10042001,10072071,10128205,30225027, 10332060,30730032,11072251,and 31110103918)National Key Basic Research Foundation of China(grants 2006CB910303 and 2011CB710904)+2 种基金National High Technology Research and Development Program of China(grants 2007AA02Z306 and 2011AA020109)Chinese Academy of Sciences(grants KJCX2-L02,KJCX2-SW-L06, 2005-1-16,KJCX2-YW-L08,Y2010030,XDA01030102,XDA04073 801)NIH Fogarty International Research Collaboration Award TW 05774-01
文摘Receptor-ligand interactions in blood flow are crucial to initiate such biological processes as inflammatory cascade,platelet thrombosis,as well as tumor metastasis.To mediate cell adhesion,the interacting receptors and ligands must be anchored onto two apposing surfaces of two cells or a cell and a substratum,i.e.,two-dimensional（2D）binding,which is different from the binding of a soluble ligand in fluid phase to a receptor,i.e.,three-dimensional（3D） binding.While numerous works have been focused on3 D kinetics of receptor-ligand interactions in the immune system,2D kinetics and its regulations have been less understood,since no theoretical framework or experimental assays were established until 1993.Not only does the molecular structure dominate 2D binding kinetics,but the shear force in blood flow also regulates cell adhesion mediated by interacting receptors and ligands.Here,we provide an overview of current progress in 2D binding and regulations,mainly from our group.Relevant issues of theoretical frameworks,experimental measurements,kinetic rates and binding affinities,and force regulations are discussed.
基金supported by the National Natural Science Foundation of China (Grants 31230027, 91642203, and 31661143044)the Frontier Science Key Project of Chinese Science Academy (Grant QYZDJ-SSW-JSC018)
文摘Blood flow inside the liver plays a key role in hepatic functions, and abnormal hemodynamics are highly correlated with liver diseases. To date, the flow field in an elementary building block of the organ, the liver lobule,is difficult to determine experimentally in humans due to its complicated structure, with radially branched microvasculature and the technical difficulties that derive from its geometric constraints. Here we established a set of 3D computational models for a liver lobule using porous media theory and analyzed its flow dynamics in normal, fibrotic,and cirrhotic lobules. Our simulations indicated that those approximations of ordinary flow in portal tracts（PTs） and the central vein, and of porous media flow in the sinusoidal network, were reasonable only for normal or fibrotic lobules.Models modified with high resistance in PTs and collateral vessels inside sinusoids were able to describe the flow features in cirrhotic lobules. Pressures, average velocities, and volume flow rates were profiled and the predictions compared well with experimental data. This study furthered our understanding of the flow dynamics features of liver lobules and the differences among normal, fibrotic, and cirrhotic lobules.
基金supported by National Natural Science Foundation of China (grants 31230027, 31110103918 and 11172207)National Key Basic Research Foundation of China (grant 2011CB710904)Strategic Priority Research Program (grants XDA01030102 and XDA04020219)
文摘Blood cell aggregation and adhesion to endothelial cells under shear flow are crucial to many biological processes such as thrombi formation, inflammatory cascade, and tumor metastasis, in which these cellular interactions are mainly mediated by the underlying receptor-ligand bindings. While theoretical modeling of aggregation dynamics and adhesion kinetics of interacting cells have been well studied separately, how to couple these two processes remains unclear. Here we develop a combined model that couples cellular aggregation dynamics and adhesion kinetics under shear flow. The impacts of shear rate （or shear stress） and molecular binding affinity were elucidated. This study provides a unified model where the action of a fluid flow drives cell aggregation and adhesion under the modulations of the mechanical shear flow and receptor-ligand interaction kinetics. It offers an insight into understanding the relevant biological processes and functions.
基金supported by National Natural Science Foundation of China Grant( 31627804,91642203, 11772345,91539119)Chinese Academy of Sciences Strategic Priority Research Program ( XDB22040101)Frontier Science Key Project( QYZDJ-SSWJSC018)
文摘Atherosclerosis or fibrosis and cirrhosis undergo chronic inflammation associated with the adhesion between neutrophils and endothelial cells(ECs)that is mediated by their respective cellular adhesive molecules on stiffened blood vessel wall or extracellular matrix(ECM)under shear flow[1-3].However,the mechanical dependence of calcium flux and trail formation in neutrophils remains unclear yet in these processes.First,the effect of substrate stiffness through ECs on neutrophil calcium spike was quantified when the individual neutrophils adhered to EC monolayer pre-placed onto stiffness-varied polyacrylamide(PA)substrate(5 or 34.88 kPa)or glass surface.Our data indicated that E-/P-selectins and ICAM-1s on HUVECs and b2-integrins,PSGL-1s,and CD44s on neutrophils were all involved in mediating neutrophil calcium spike in a stiffness-dependent manner,in which the increase of substrate stiffness enhanced the calcium intensity and spike number.Such stiffness-dependent calcium response is associated with selectin-induced b2-integrin activation through Syk/Src signaling pathway and the F-actin/myosin II function.Moreover,tension-activated calcium ion channels displayed critical roles in initiating stiffness-dependent calcium spike [4].Second,the trail formation of neutrophils to ECs monolayer pre-placed onto the same PA substrate were also tested under shear flow.Live fluorescence imaging showed that neutrophils are able to form long membrane tethers during migration and subsequently leave behind membranous long-lasting trails under shear,which are enriched in LFA-1,Mac-1,and CD44.Moreover,the formation of the trails was inhibited by blocking LFA-1s and Mac-1s,suggesting an important role forβ2-integrins in the trial formation.The recruitment of monocytes was inhibited when pre-blocking ICAM-1s on flowing monocytes,indicating that the neutrophil’s trails employβ2-integrin-ICAM-1 binding to recruit the monocytes.Intriguingly,both the length and the area of the trails increase with increasing substrate stiffness,resulting in the enhanced monocyte recruitment.Inhibition of actin binding protein Arp2/3 impairs the trail formation and dramatically decreases the neutrophil-dependent monocyte recruitment.These data provide an insight into understanding how stiffening of vascular wall could regulate the calcium flux of adhered neutrophils and thus the immune responses in atherosclerosis.They also imply that local mechanical microenvironment is remodeled with the migration of neutrophils,leaving the trails presented to induce and regulate monocyte recruitment.All the results are meaningful in elucidating the occurrence and development of atherosclerosis or fibrosis from the viewpoint of mechanotransduction and also for the potential intervention of cardiovascular disease progress.
基金This work was supported by National Key Research and Development Program of China Grant 2016YFA0501601National Natural Science Foundation of China Grants 31661143044,and 31300776+1 种基金Strategic Priority Research Program and Frontier Science Key Project of Chinese Academy of Sciences Grants XDB22040101 and QYZDJ-SSW-JSC018the Visiting Scholar Foundation of the Key Laboratory of Biorheological Science and Technology(Chongqing University),Ministry of Education(CQKLBST-2015-002).
文摘Neutrophil(PMN)accumulation on liver sinusoidal endothelial cells(LSECs)is crucial to pathogen clearance and tissue damage in the liver sinusoids and controlled by a series of adhesion molecules expressed on the surface of PMNs and LSECs.The role of lymphocyte function-associated antigen-1(LFA-1)and macrophage-1 antigen(Mac-1)in this process is still contentious.Here we compared the dynamic force spectra of the binding ofβ2 integrin to intercellular adhesion molecule-1(ICAM-1)on LSECs using atomic force microscopy(AFM)and performed free and steered molecular dynamics(MD)simulations to analyze their structural bases of LFA-1-or Mac-1-I-domain and ICAM-1-D1 or D3 pair in their force spectra.Our AFM data suggest that the mechanical strength of LFA-1-ICAM-1 bond is significantly stronger than that of Mac-1-ICAM-1 bond,implying a dominate role for LFA-1 to mediate PMN adhesion under shear flow.MD simulations indicated that spontaneous dissociation of Mac-1-I-domain vs.ICAMD3-domain is slower with the stronger interaction energy than that for LFA-1 I-domain vs.ICAM-D1-domain and that the rupture force for Mac-1 is lower than that for LFA-1,which are in qualitative agreement with the above experimental observations.These data indicate that the biomechanical features of LFA-1 and Mac-1 to mediate PMN adhesion on LSECs in vitro are similar with those in other tissues like cerebrovascular endothelium,while Mac-1-mediated PMN recruitment in liver sinusoids may stem from the slow blood flow in vivo.These findings further the understandings of PMN recruitment under shear flow in liver sinusoids.
基金supported by the National Natural Science Foundation of China (Grants 32130061 and 12172366)。
文摘Membrane fusion is an important process by which biological membranes perform their life activities. Simulations show that the membrane fusion process happens mainly through three pathways, where the Stalk-Pore hypothesis, in which two membranes come into close contact to form a stalk to a hemifusion intermediate, and then the fusion pore opens to achieve completely fusion, is widely accepted, and there exist two free energy barriers that break the current structural steady state for lipid rearrangement. Factors of lipid composition, mechanical environment, protein and ion have regulatory roles in the membrane fusion process by effecting membrane curvature structurally and the free energy barriers from energetic perspective. Meanwhile, many theoretical models, represented by the Helfrich model, have been proposed to predict the membrane fusion process. In this paper, we review the research process of membrane fusion and mainly introduce the dynamics of membrane fusion, regulation factors and typical theoretical models.
