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| 1 | Mechanical microenvironments of living cells: a critical frontier in mechanobiology显示文摘The fields of biomechanics and mechanobiology have long been predicated on the premise that mechanics governs cell behavior. However, over the past few years, a growing body of evidence has suggested that the mechanical environment very close to cells–the cell microenvironment–plays the most important role in determining what a cell feels and how it responds to tissue-level stimuli. To complicate matters further, cells can actively manipulate their microenvironments through pathways of recursive mechanobiological feedback. Harnessing this recursive behavior to understand and control cell physiology and pathophysiology is a critical frontier in the field of mechanobiology. Recent results suggest that the key to opening this scientific frontier to investigation and engineering application is understanding a different frontier: the physical frontier that cells face when probing their mechanical microenvironments. | Guoyou Huang Feng Xu Guy M. Genin Tian Jian Lu | 2019 | Acta Mechanica Sinica2019，35，2： | 5 |
| 2 | Measurement of Neutron Capture Cross Section for ^(180)Hf | Chen Jinxiang Shi Zhaomin Tang Guoyou Zhang Guohui Institute of Heavy Ion Physics,Peking University,Beijing 100871Lu Hanlin Han Xiaogang Huang Xiaolong China Institute of Atomic Energy,P.O.Box 275(3),Beijing 102413 | 1997 | Chinese journal of nuclear physics1997，，2： | 3 |
| 3 | The Matrix Stiffness and Physical Confinement of Hydrogel Microchannel Jointly Induce the Mesenchymal-Amoeboid Transition for Cancer Cell Migration显示文摘The migration mode transition of cancer cell enhances its invasive capability and the drug resistance,where physical confinement of cell microenvironment has been revealed to induce the mesenchymal-amoeboid transition(MAT).However,most existing studies are performed in PDMS microchannels,of which the stiffness is much higher than that of most mammalian tissues.Therefore,the amoeboid migration transition observed in these studies is actually induced by the synergistic effect of matrix stiffness and confinement.Since the stiffness of cell microenvironment has been reported to influence the cell migration in 2D substrate,the decoupling of stiffness and confinement effects is thus in need for elucidating the underlying mechanism of MAT.However,it is technically challenging to construct microchannels with physiologically relevant stiffness and channel size,where existing microchannel platforms with physiological relevance stiffness are all with>10μm channel width.Such size is too wide to mimic the physical confinement that migrating cancer cells confront in vivo,and also larger than the width of PDMS channel,in which the MAT of cancer cell was observed.Therefore,an in vitro cell migration platform,which could mimic both stiffness and confinement of the native physical microenvironment during cancer metastasis,could profoundly contribute to researches on cancer cell migration and cellular mechanotransduction.In this paper,we overcome the limitations of engineering soft materials in microscale by combining the collagen-alginate hydrogel with photolithography.This enables us to improve the accuracy of molded microchannel,and thus successfully construct a 3D microchannel platform,which matches the stiffness and width ranges of native environmental confinement that migrating cancer cells confront in vivo.The stiffness(0.3~20 kPa),confinement(channel width:3.5~14μm)and the adhesion ligand density of the microchannel can be tuned independently.Interestingly,using this platform,we observed that the migration speed of cancer cell is influenced by the synergistic effect of channel stiffness and width,and the increasing stiffness reverses the effect of channel width on the migration speed of cancer cells.In addition,MAT has a strong correlation with the channel stiffness.These findings make us reconsider the widely accepted hypothesis:physical confinement can induce MAT.Actually,this transition can only occur in stiff confined microenvironment not in soft one.For soft microchannels,the compliance of the channel walls could cause little cell/nucleus deformation,and the MAT could not be induced.To further investigate the mechanism of MAT,we developed a computational model to simulate the effect of nucleus deformation on MAT.With the model,we found that deforming the cell nuclear by decreasing the nucleus stiffness will reduce the cellmigration speed.This implies that nuclear stiffness plays an important role in the regulation of cancer migration speed and thus MAT in microchannels.The effect of channel stiffness on MAT and migration speed as observed in our experiment could partially explain previous findings reported in the literature,where the increasing matrix stiffness of tumor microenvironment promotes cancer metastasis.Our observations thus highlight the critical role of cell nuclear deformation not only in MAT,but also in regulating cellular mechanotransduction and cell-ECM interactions.This developed platform is capable of mimicking the native physical microenvironment during metastasis,providing a powerful tool for high-throughput screening applications and investigating the interaction between cancer migration and biophysical microenvironment. | Meng Wang Bo Cheng Yaowei Yang Han Liu Guoyou Huang Fei Li Feng Xu | 2019 | 医用生物力学2019，34，A01： | 2 |
| 4 | Effect of viscoelasticity on skin pain sensation显示文摘Pain sensation may appear under long-lasting mechanical stimulation. Although people have the experience that pain sensation generally decreases with time while the stimulation remains, the underlying mechanism remains elusive. We experimentally studied the thermal and strain ratedependent viscoelastic behavior of skin in uniaxial stretch and numerically investigated the effects of temperature and strain rate on pain sensation. The results indicate that the viscosity of skin tissue decreases with increasing temperature and reducing strain rate, which subsequently decreases the discharge frequency of skin nociceptor and thus relieves the pain sensation. The results would contribute to the understanding of pain relief mechanism and optimizing for mechanical treatment. | Fusheng Liu Chenghai Li Shaobao Liu Guy M.Genin Guoyou Huang TianJian Lu Feng Xu | 2015 | Theoretical & Applied Mechanics Letters2015，5，6： | 1 |
| 5 | A Mechanoelectrical Coupling Model of Neurons under Stretching显示文摘Introduction Neurons are situated in a microenvironment composed of various biochemical and biophysical cues,where stretching is thought to have a major impact on neurons.For instance,during a moderate traumatic brain impact,the injury region in axons exhibits significant longitudinal strain;and in a rat model of spinal cord injury,the most severe axonal injury is located in the largest strain region.Stretching may result in microstructural changes in neural tissue and further leading to abnormal electrophysiological function.Hence,it is of great importance to understand the coupled mechanoelectricalbehaviors of neurons under stretching.In spite of significant experimental efforts,the underlying mechanism remains elusive,more works are needed to provide a detailed description of the process that leads to the observed phenomena.Mathematical modeling is a powerful tool that offers a quantitative description of the underlying mechanism of an observed biological phenomenon,including mechanical and electrophysiological behaviors of neurons.Thus,we developed a mechanoelectrical coupling model of neurons under stretching in this study.Mathematical model The mathematical model consists of three submodels,i.e.,the mechanical submodel,the mechanoelectrical coupling submodel and the electrophysiological submodel.The mechanical submodel deals with the relationship between stretching and the deformation of axons,which has specially considered the plastic deformation of axons.The electrophysiological submodel characterizes the feature of neuronal action potential(AP),which is based on the classical H-H model and the cable theory.The mechanoelectrical coupling submodel links the mechanical and electrophysiological submodels through strain-induced equivalent circuit parameter alteration and ion channel injury.Besides,we have discussed a more general deformation condition,where an expanded model coupling the axonal deformation and electrophysiology alteration was explored.As the most essential parameters in an electrophysiological assessment,the amplitude of the AP,the neuronal firing frequency and the electrophysiological signal conduction velocity,which could be affected by stretching,were used as outputs of the model.Results&discussion To understand the mechanoelectrical coupling of neurons under stretching,we developed a mechanoelectrical coupling model.To verify the model,we simulated a slow stretching on an axon following the experimental study in the literature,we observed that as the strain increases,the peak AP declines faster,which is consistent with the experimental data.Moreover,the reduced AP cannot be restored to the original peak,implying that the damage is irreversible.The simulation results also predict that strain induces a more frequent neuronal firing and a faster conduction.In a realistic situation,in addition to stretching,the loading condition is very complicated,which may induce complex axonal deformation(e.g., necking and swelling along the axons).We also simulated such necking deformation impairment and observed that the AP amplitude decreases at the necking region and recovers after that,indicating a blockage of the AP;and the conduction velocity decreases with the increase in deformation degree.Conclusions In this study,we developed a mechanoelectrical coupling model of neurons under stretching with consideration of axonal plastic deformation.With the model,we found that the effect of mechanical loading on electrophysiology mainly manifests as decreased membrane AP amplitude,a more frequent neuronal firing and a faster electrophysiological signal conduction.The model predicts not only stretch-induced injury but also a more gene ral necking deformation case,which may someday be revealed in future by experiments,providing a reference for the prediction and regulation of neuronal function under mechanical loadings. | Jin Tian Guoyou Huang Min Lin Jinbin Qiu Baoyong Sha Tian Jian Lu Feng Xu | 2019 | 医用生物力学2019，34，A01： | 0 |
| 6 | Matrix Stiffness Controls Cardiac Fibroblast Differentiation Through Regulating YAP via AT1R显示文摘Cardiac fibrosis is a common pathway to heart injury and failure,where continued activation of cardiac fibroblasts(CFs)during myocardium damage causes excessive deposition of the extracellular matrix and thus increases matrix stiffness.Increasing evidence has shown that stiff matrix plays an important positive role in promoting CF differentiation and cardiac fibrosis,with several signaling factors medicating CF mechanotransduction already identified.However,key moleculesthat perceive matrix stiffness to regulate CF differentiation remain to be fully defined.Recently,Hippo pathway transcriptional coactivators,i.e.,Yes-associated protein(YAP)and transcriptional coactivator with PDZ-binding motif(TAZ),have been found to work as mechanical signal transductors.Importantly,it has shown that YAP plays important roles in various types of fibrosis.Despite these findings,the role of YAP in CF mechanotransduction and cardiac fibrosis still remains elusive.Moreover,several several types of GPCRs have also been found to enable cells to sense mechanical cues,however,the relationship between these GPCRs and YAP in cell mechanotransduction is still not clear.Our recent work demonstrated that blocking of angiotensin II type 1 receptor(AT1R,the first GPCRs found to be mechanosensors)with losartan significantly inhibited the differentiation of CFs to myofibroblasts induced by stiff substrate.Taken these findings into account,we speculate that YAP may work as an important downstream signaling molecule of AT1R in mediating matrix stiffness-induced CF differentiation.In this work,we first characterized the expression of YAP in normal control(NC)and myocardial infarct(Ml)tissues of rats by using immunohistochemistry,immunofluorescence and Western blot analysis.We then investigated the role of YAP in matrix stiffness-induced CF differentiation in vitro by culturing CFs on mechanically tunable gelatin hydrogels.Finally,we explored the relationship between YAP and AT1R in CF mechanotransduction by selective transfection and inhibition experiments.The expression of YAP andα-SMA in cultured CFs were evaluated with immunofluorescence staining,Western blot and real-time quantitative PCR analysis.Immunohistochemical analysis revealed that both YAP andα-SMA significantly increased in Ml tissue compared with NC tissue.The expression and nuclear localization of YAP increased in CFs cultured on stiff matrix.YAP-deficient CFs cultured on soft and stiff matrix both showed decreased expression ofα-SMA.Meanwhile,YAP-overexpressing CFs cultured on soft and stiff matrix both showed increased expression ofα-SMA.Blocking of AT1R decreased the expression levels ofα-SMA and YAP and thus affected the responses of CFs to matrix stiffness.To sum up,our results identified an important role of YAP in mediating matrix stiffness-induced CF differentiation and also established the YAP pathway as an important signaling branch downstream of AT1R in CF mechanotransduction.This study may help to better understand the mechanism of fibrotic mechanotransduction and inspire the development of new approaches for treating cardiac fibrosis. | Lele Niu Yuanbo Jia Mian Wu Han Liu Yan Hu Feng Xu Guoyou Huang | 2019 | 医用生物力学2019，34，A01： | 0 |
| 7 | Development of a micro-indentation device for measuring the mechanical properties of soft materials显示文摘Indentation is a simple and nondestructive method to measure the mechanical properties of soft materials,such as hydrogels,elastomers and soft tissues.In this work,we have developed a micro-indentation system with high-precision to measure the mechanical properties of soft materials,where the shear modulus and Poisson’s ratio of the materials can be obtained by analyzing the load–relaxation curve.We have validated the accuracy and stability of the system by comparing the measured mechanical properties of a polyethylene glycol sample with that obtained from a commercial instrument.The mechanical properties of another typical polydimethylsiloxane sample submerged in heptane are measured by using conical and spherical indenters,respectively.The measured values of shear modulus and Poisson’s ratio are within a reasonable range. | Xiang He Pengfei Wang Guoyou Huang Shaobao Liu Minglong Xu Feng Xu TianJian Lu | 2013 | Theoretical & Applied Mechanics Letters2013，3，5： | 0 |
| 8 | Decrease of Matrix Plasticity Promotes Fibroblast Activation in Fibrosis显示文摘This work identified the important role of matrix mechanical plasticity in mediating fibroblast activation.Many existing studies have highlighted the important effects of biochemical cues(e.g.,transforming growth factor-β1)and mechanicalstiffness on fibroblast activation.Our results indicated that self-assembled collagen hydrogels showed high plasticity and in which fibroblasts remain undifferentiated.However,when we decreased the plasticity of collagen hydrogels by increasing covalent crosslinking,fibroblasts showed a significant fibrotic response as reflected by the increasedα-SMA expression.Since the material systems we constructed have low and the same initial modulus,this process is stiffness independent.Although it has been reported that covalently crosslinked hydrogels are more difficult to degrade and matrix degradability has an important impact on cell behaviors,no significant changes of fibroblast activation were observed when proteases were broadly inhibited in our experiments.Importantly,the hydrogels we constructed showed similar plastic behaviors under creep and recovery tests compared to native normal and fibrotic tissues.These highlight the importance of matrix plasticity in mimicking the mechanical microenvironment of native fibrotic tissues.Mechanistically,we found that the enhanced fibroblast activation in low plastic matrix is mediated through integrin-actin pathway and nuclear localization of YAP.In high plastic collagen,matrix cannot provide effective resistance to actin contraction because of the rupture of weak crosslinks and the slippage of local fibers.On the contrary,in low plastic collagen,deformation energy can be stored in the network due to the existence of strong covalent crosslinks,thus enabling the build-up of cell traction and the formation of a robust cell-matrix interaction.Experiments of inhibiting or promoting cytoskeletal contractility and CGMD simulation both verified the above points.Our results clarify plasticity changes on the development of fibrotic diseases and highlight plasticity as an important mechanical cue in understanding cell-matrix interactions. | Yuanbo Jia Yanzhong Wang Lele Niu Hang Zhang Jin Tian Dengfeng Gao Xiaohui Zhang Tian Jian Lu Jin Qian Guoyou Huang Feng Xu | 2019 | 医用生物力学2019，34，A01： | 0 |
| 9 | Genome-wide selection and introgression of Chinese rice varieties during breeding显示文摘China is the largest rice-producing country,but the genomic landscape of rice diversity has not yet been clarified.In this study,we re-sequence 1070 rice varieties collected from China(400)and other regions in Asia(670).Among the six major rice groups(aus,indica-I,indica-II,aromatic,temperate japonica,and tropical japonica),almost all Chinese varieties belong to the indica-II or temperate japonica group.Most Chinese indica varieties belong to indica-II,which consists of two subgroups developed during different phases of rice breeding.The genomic segments underlying the differences between these subgroups span36.32 Mb.The Chinese japonica rice varieties fall into the temperate japonica group,consisting of two subgroups based on their geographical distribution.The genomic segments underlying the differences between these subgroups span 27.69 Mb.These differentiated segments in the Chinese indica varieties span 45 genes with nonsynonymous mutations that are closely related to variations in plant height and grain width.Fifty-four genes with nonsynonymous mutations are associated with the differences in heading date between the two Chinese japonica subgroups.These findings provide new insights into rice diversity in China that will facilitate the molecular breeding. | Jinyue Ge Junrui Wang Hongbo Pang Fei Li Danjing Lou Weiya Fan Ziran Liu Jiaqi Li Danting Li Baoxuan Nong Zongqiong Zhang Yanyan Wang Jingfen Huang Meng Xing Yamin Nie Xiaorong Xiao Fan Zhang Wensheng Wang Jianlong Xu Sung Ryul Kim Ajay Kohli Guoyou Ye Weihua Qiao Qingwen Yang Xiaoming Zheng | 2022 | Journal of Genetics and Genomics2022，49，5： | 0 |
| 10 | CHCHD2 Thr61Ile mutation impairs F1F0-ATPase assembly in in vitro and in vivo models of Parkinson's disease显示文摘Mitochondrial dysfunction is a significant pathological alte ration that occurs in Parkinson's disease(PD),and the Thr61lle(T61I)mutation in coiled-coil helix coiled-coil helix domain containing 2(CHCHD2),a crucial mitochondrial protein,has been reported to cause Parkinson's disease.FIFO-ATPase participates in the synthesis of cellular adenosine triphosphate(ATP)and plays a central role in mitochondrial energy metabolism.However,the specific roles of wild-type(WT)CHCHD2 and T611-mutant CHCHD2 in regulating F1FO-ATPase activity in Parkinson's disease,as well as whether CHCHD2 or CHCHD2 T61I affects mitochondrial function through regulating F1FO-ATPase activity,remain unclea r.Therefore,in this study,we expressed WT CHCHD2 and T61l-mutant CHCHD2 in an MPP^(+)-induced SH-SY5Y cell model of PD.We found that CHCHD2 protected mitochondria from developing MPP^(+)-induced dysfunction.Under normal conditions,ove rexpression of WT CHCHD2 promoted F1FO-ATPase assembly,while T61I-mutant CHCHD2 appeared to have lost the ability to regulate F1FO-ATPase assembly.In addition,mass spectrometry and immunoprecipitation showed that there was an interaction between CHCHD2 and F1FO-ATPase.Three weeks after transfection with AAV-CHCHD2 T61I,we intraperitoneally injected 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into mice to establish an animal model of chronic Parkinson's disease and found that exogenous expression of the mutant protein worsened the behavioral deficits and dopaminergic neurodegeneration seen in this model.These findings suggest that WT CHCHD2 can alleviate mitochondrial dysfunction in PD by maintaining F1F0-ATPase structure and function. | Xiang Chen Yuwan Lin Zhiling Zhang Yuting Tang Panghai Ye Wei Dai Wenlong Zhang Hanqun Liu Guoyou Peng Shuxuan Huang Jiewen Qiu Wenyuan Guo Xiaoqin Zhu Zhuohua Wu Yaoyun Kuang Pingyi Xu Miaomiao Zhou | 2024 | Neural Regeneration Research2024，19，1： | 0 |
| 11 | Dynamic Change of Matrix Stiffness Switches Astrocyte Phenotype in Three Dimensions显示文摘Background Damage to the central nervous system(CNS)usually leads to the activation of astrocytes,followed by glial scar formation.For years,glial scar has been thought as a major obstacle for successful axon regeneration.However,increasing evidence suggests a beneficial role for this scar tissue as part of the endogenous local immune regulation and repair process.Surprisingly,in contrast to scars in other tissues,glial scars(mainly consist of reactive astrocytes)in both rat cortex and spinal cord were recently found to be significantly softer than healthy CNS tissues.Naive astrocytes have been found to change their phenotype to reactive astrocytes and gradually into scar-forming astrocytes,upregulating the astrocyte marker glial fibrillary acidic protein(GFAP),vimentin,and inflammatory proteins in almost all known brain disorders.Such phenotype transformation process has been widely thought unidirectional or irreversible.However,recent research revealed the environment-dependent plasticity of astrocyte phenotypes,with reactive astrocytes could revert in retrograde to naive astrocytes in proper microenvironment.In consideration of the important roles of mechanical cues in CNS and the unique softening behavior of glial scars,it is of great interesting to study the effects of dynamic changes of matrix stiffness on astrocyte phenotypic switch.Materials&methods Primary astrocyes were isolated from the cortex of SpragueDawley(SD)rats at PI.After cultured for 2 weeks,astrocytes were encapsulated into a set of three-dimensional(3D)hybrid hydrogel system composed of type I collagen and alginate.Immunofluorescence and Western blot expression analysis were applied for characterizting cell responses to different and dynamically changed matrix stiffness.A molecular dynamics model was developed for simulation.Results&discussion In this work,we established an in-vitro model to study the effects of dynamic changes of matrix stiffness on astrocyte phenotypic switchings in 3D.To simulate native cellular environment,we fabricated a set of hybrid hydrogel system composed of type I collagen and alginate.The stiffness of the hybrid hydrogels was demonstrated to be dynamically changed by adding calcium chloride or sodium citrate to crosslink or decrosslink alginate,respectively.Using 3D culture models,we showed that the decrease of matrix stiffness could promote astrocyte activation,with upregulated GFAP and IL-1β.In addition,3D cultured astrocytes spread greater with decreasing matrix stiffness.Moreover,we surprisingly found that astrocyte phenotype could be switched by dynamically changing matrix stiffness.Specifically,matrix stiffening reverted the activation of astrocytes,whereas matrix softening induced astrocyte activation.We further demonstrated that matrix stiffness-induced astrocyte activation was mediated through cytoskeletal tension and YAP protein.To some extent,YAP inhibition enhanced the responses of astrocytes to matrix stiffness.These may guide researchersto re-examine the role of matrix stiffness in reactive astrogliosis in vivo,and inspire the development of novel therapeutic approach for reducing glial scar following injury,enabling axonal regrowth and improving functional recovery by exploiting the benefits of mechanobiology studies.Conclusions Taken together,our results clarify the effects of matrix stiffness and its dynamic changes on phenotypic swtich of astrocytes in three dimensions and reveal environmental factors that regulate astrocytic phenotype transformation process,which may provide potential therapeutic approach for CNS injury. | Yan Hu Jin Tian Jinbin Qiu Dayun Feng Guoyou Huang Feng Xu | 2019 | 医用生物力学2019，34，A01： | 0 |
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