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matrix stiffness exacerbates the proinflammatory responses of vascular smooth muscle cell through the DDR1-DNMT1 mechanotransduction axis

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Bioactive Materials 2022年第11期7卷 406-424页

作者： Jin Wang Si-an Xie Ning Li Tao Zhang Weijuan Yao Hucheng Zhao Wei Pang Lili Han Jiayu Liu Jing Zhou Department of Physiology and Pathophysiology School of Basic Medical SciencesHemorheology CenterSchool of Basic Medical SciencesPeking UniversityBeijingPR China Key Laboratory of Molecular Cardiovascular Science Ministry of EducationBeijingPR China National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors ResearchPeking UniversityBeijingPR China Department of Gastroenterology Beijing Friendship HospitalCapital Medical UniversityNational Clinical Research Center for Digestive DiseaseBeijing Digestive Disease CenterBeijing Key Laboratory for Precancerous Lesion of Digestive DiseaseBeijingPR China Center for Biomechanics and Bioengineering Key Laboratory of Microgravity(National Microgravity Laboratory)And Beijing Key Laboratory of Engineered Construction and MechanobiologyInstitute of MechanicsChinese Academy of SciencesBeijingPR China School of Engineering Sciences University of Chinese Academy of SciencesBeijingPR China Department of Vascular Surgery Peking University People’s HospitalBeijingPR China Institute of Biomechanics and Medical Engineering School of Aerospace EngineeringTsinghua UniversityBeijingPR China

Vascular smooth muscle cell (vSMC) is highly plastic as its phenotype can change in response to mechanical cues inherent to the extracellular matrix (ECM). VSMC may be activated from its quiescent contractile phenotype to a proinflammatory phenotype, whereby the cell secretes chemotactic and inflammatory cytokines, e.g. MCP1 and IL6, to functionally regulate monocyte and macrophage infiltration during the development of various vascular diseases including arteriosclerosis. Here, by culturing vSMCs on polyacrylamide (PA) substrates with variable elastic moduli, we discovered a role of discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that binds collagens, in mediating the mechanical regulation of vSMC gene expression, phenotype, and proinflammatory responses. We found that ECM stiffness induced DDR1 phosphorylation, oligomerization, and endocytosis to repress the expression of DNA methyltransferase 1 (DNMT1), very likely in a collagen-independent manner. The DDR1-to-DNMT1 signaling was sequentially mediated by the extracellular signal-regulated kinases (ERKs) and p53 pathways. ECM stiffness primed vSMC to a proinflammatory phenotype and this regulation was diminished by DDR1 inhibition. In agreement with the in vitro findings, increased DDR1 phosphorylation was observed in human arterial stiffening. DDR1 inhibition in mouse attenuated the acute injury or adenine diet-induced vascular stiffening and inflammation. Furthermore, mouse vasculature with SMC-specific deletion of Dnmt1 exhibited proinflammatory and stiffening phenotypes. Our study demonstrates a role of SMC DDR1 in perceiving the mechanical microenvironments and down-regulating expression of DNMT1 to result in vascular pathologies and has potential implications for optimization of engineering artificial vascular grafts and vascular networks.

关键词： matrix stiffness Inflammation DDR1 DNMT1 Mechanotransduction

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Activation of Piezo1 contributes to matrix stiffness-induced angiogenesis in hepatocellular carcinoma

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Cancer Communications 2022年第11期42卷 1162-1184页

作者： Miao Li Xi Zhang Mimi Wang Yaohui Wang Jiali Qian Xiaoxia Xing Zhiming Wang Yang You Kun Guo Jie Chen Dongmei Gao Yan Zhao Lan Zhang Rongxin Chen Jiefeng Cui Zhenggang Ren Liver Cancer Institute Zhongshan HospitalFudan University&Key Laboratory of Carcinogenesis and Cancer InvasionMinistry of EducationShanghai 200032P.R.China Department of Radiology Shanghai Cancer CenterFudan UniversityShanghai 200032P.R.China Department of Endocrinology Huashan HospitalFudan UniversityShanghai 200032P.R.China Department of Oncology Zhongshan HospitalFudan UniversityShanghai 200032P.R.China

Background:Despite integrin being highlighted as a stiffness-sensor molecule in matrix stiffness-driven angiogenesis,other stiffness-sensor molecules and their mechanosensory pathways related to angiogenesis in hepatocellular carcinoma(HCC)remain obscure.Here,we explored the interplay between Piezo1 and integrinβ1 in the mechanosensory pathway and their effects on HCC angiogenesis to better understand matrix stiffness-induced angiogenesis.Methods:The role of Piezo1 in matrix stiffness-induced angiogenesis was investigated using orthotopic liver cancer SD rat models with high liver stiffness background,and its clinical significance was evaluated in human HCC tissues.matrix stiffness-mediated Piezo1 upregulation and activation were assayed using an in vitro fibronectin(FN)-coated cell culture system with different stiffness,Western blotting and Ca^(2+)probe.The effects of shPiezo1-conditioned medium(CM)on angiogenesis were examined by tube formation assay,wound healing assay and angiogenesis array.The underlying mechanism by which Piezo1 participated in matrix stiffness-induced angiogenesis was analyzed by microRNA quantitative real-time polymerase chain reaction(qRT-PCR),matrix stiffness measurement,dual-luciferase reporter assay,ubiquitination assay and co-immunoprecipitation.Results:Increased matrix stiffness significantly upregulated Piezo1 expression at both cellular and tissue levels,and high expression of Piezo1 indicated an unfavorable prognosis.High matrix stiffness also noticeably enhanced the activation level of Piezo1,similar to its expression level.Piezo1 knockdown significantly suppressed tumor growth,angiogenesis,and lung metastasis of HCC rat models with high liver stiffness background.shPiezo1-CM from HCC cells attenuated tube formation and migration abilities of vascular endothelial cells remarkably,and analysis of differentially expressed pro-angiogenic factors revealed that Piezo1 promoted the expression and secretion of vascular endothelial growth factor(VEGF),CXC chemokine ligand 16(CXCL16)and

关键词： hepatocellular carcinoma matrix stiffness angiogenesis Piezo1 HIF-1αubiquitination

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UV-induced senescence of human dermal fibroblasts restrained by low-stiffness matrix by inhibiting NF-κB activation

Engineered Regeneration

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Engineered Regeneration 2022年第4期3卷 365-373页

作者： Xuefeng Yao Huaqiong Li Liping Chen Lay Poh Tan School of Materials Science and Engineering Nanyang Technological University639798Singapore Zhejiang Engineering Research Center for Tissue Repair Materials Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang 325000PR China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)WenzhouZhejiang 325000PR China

As a hallmark of skin aging,senescent human dermal fibroblasts(HDFs)are known to lose the ability to divide.However,they can still interact with their cellular environment and the surrounding matrix.As the skin ages,the progressive slowing down of HDFs function decreases the skin’s structural integrity,which is more serious than if there is the dermal collagen matrix eroded.This leads to matters of the unbalanced barrier under the skin,skin fragility,inadequate wound healing,as well as other cosmetic issues.It is also well documented that skin aging comes with significant stiffness increases.Therefore,understanding the interactions between HDFs and the surrounding microenvironments during senescence may provide insights into skin aging.Here we aim to inves-tigate matrix stiffness’effect on HDF senescence and elucidate possible mechanisms that make HDFs senescent.In our experiments,HDFs were cultivated on Polydimethylsiloxane(PDMS)with various stiffnesses and exposed to UV light to trigger senescence.Results show that HDFs are significantly affected by senescence when cultured on a matrix with stiffness.However,the cells are not significantly affected when cultured on a low stiffness matrix.The following characterization revealed cells cultured on stiffsubstrates under UV exposure had stimu-lated the nucleus factor kappa-B(NF-κB)activation.In contrast,cells on a matrix of softness only displayed low activation of NF-κB.NF-κB activity suppression with ammonium pyrrolidine dithiocarbamate(PDTC)decreases UV-induced HDFs senescence on stiffsubstrates.Taken together,we demonstrated that soft matrix defends HDFs against ultraviolet-induced senescence by inhibiting the activation of NF-κB.

关键词： Human dermal fibroblasts matrix stiffness Senescence NF-κB

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matrix stiffness-Induced Transcriptome Alterations and Regulatory Mechanisms Revealed by RNA-Seq in Endothelial Cells

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Journal of Biomaterials and Nanobiotechnology 2022年第3期13卷 61-79页

作者： Chao Zhang Xiaomei Han Jin Xu Yue Zhou School of Biomedical Engineering Shanghai Jiao Tong University Shanghai China

Changes in vascular stiffness are associated with the development and progression of many diseases, especially in cardiovascular disease. However, the effect of vascular stiffness on the endothelial cells (ECs) is not fully understood. Therefore, this study aims to determine the gene expression changes of ECs cultured on the matrices with different stiffness (1 kPa and 40 kPa, respectively) by RNA-seq, thereby broadening the knowledge between mechanics and biology. We obtained 1775 differentially expressed genes (DEGs) by RNA-seq, with 450 up-regulated and 1325 down-regulated DEGs in ECs cultured on soft matrix (1 kPa) compared to those cultured on stiff matrix (40 kPa). After that, we performed a series of functional enrichment analyses based on DEGs and found that DEGs were enriched in many signaling pathways like adhesion junction. Furthermore, transcription factor (TF) target gene prediction analysis and protein-protein interaction (PPI) analysis were also conducted. We found that mechanotransduction signaling related TFs such as BRD4 are involved in. And in the PPI analysis, some genes encoding extracellular matrix proteins such as fibronectin 1 (FN1) were identified as the hub genes. In order to confirm the RNA-seq results, we performed real-time qPCR analysis on the genes of interest, including FN1, collagen α2 (IV) chain, matrix metalloproteinase-14 and integrin α5, and found that the expression levels of all these genes were down-regulated on soft matrix, suggesting that soft matrix caused by pathological conditions may directly attenuate vascular barrier function. This study offers the insights about the effects of physical stimulation on cells, paving a way for vascular tissue engineering, regenerative medicine, disease modeling and therapies.

关键词： Endothelial Cells matrix stiffness RNA-Seq Cell-Cell Junctions Extracellular matrix

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Pathological matrix stiffness promotes cardiac fibroblast differentiation through the POU2F1 signaling pathway

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Science China(Life Sciences) 2021年第2期64卷 242-254页

作者： Mingzhe Li Jimin Wu Guomin Hu Yao Song Jing Shen Junzhou Xin Zijian Li Wei Liu Erdan Dong Ming Xu Youyi Zhang Han Xiao Department of Cardiology and Institute of Vascular Medicine Peking University Third Hospital/NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides/Key Laboratory of Molecular Cardiovascular ScienceMinistry of Education/Beijing Key Laboratory of Cardiovascular Receptors ResearchBeijing 100191China Division of Cardiovascular Sciences Faculty of Biology Medicine and HealthUniversity of ManchesterManchester M139PTUK Institute of Cardiovascular Sciences Health Science CenterPeking UniversityBeijing 100191China

Cardiac fibroblast(CF)differentiation into myofibroblasts is a crucial cause of cardiac fibrosis,which increases in the extracellular matrix(ECM)stiffness.The increased stiffness further promotes CF differentiation and fibrosis.However,the molecular mechanism is still unclear.We used bioinformatics analysis to find new candidates that regulate the genes involved in stiffnessinduced CF differentiation,and found that there were binding sites for the POU-domain transcription factor,POU2F1(also known as Oct-1),in the promoters of 50 differentially expressed genes(DEGs)in CFs on the stiffer substrate.Immunofluorescent staining and Western blotting revealed that pathological stiffness upregulated POU2F1 expression and increased CF differentiation on polyacrylamide hydrogel substrates and in mouse myocardial infarction tissue.A chromatin immunoprecipitation assay showed that POU2F1 bound to the promoters of fibrosis repressors IL1R2,CD69,and TGIF2.The expression of these fibrosis repressors was inhibited on pathological substrate stiffness.Knockdown of POU2F1 upregulated these repressors and attenuated CF differentiation on pathological substrate stiffness(35 kPa).Whereas,overexpression of POU2F1 downregulated these repressors and enhanced CF differentiation.In conclusion,pathological stiffness upregulates the transcription factor POU2F1 to promote CF differentiation by inhibiting fibrosis repressors.Our work elucidated the crosstalk between CF differentiation and the ECM and provided a potential target for cardiac fibrosis treatment.

关键词： fibroblast differentiation matrix stiffness POU2F1 cardiac fibrosis transcription factor

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Substrate stiffness and Topography Affect the Morphology of Human Fibroblasts in Mechanical Microenvironment

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上海交通大学学报:英文版 2023年第4期28卷 495-506页

作者：刘阳王雅靖温大渭张全有王立安美文刘勇 Institute of Biomedical Engineering Shanxi Key Laboratory of Material Strength&Structural ImpactResearch Center for Nano-Biomaterials&Regenerative MedicineCollege of Biomedical EngineeringTaiyuan University of TechnologyTaiyuan 030024China Department of Nuclear Medicine First Hospital of Shanxi Medical UniversityTaiyuan 030001China Dermatology Department Shanxi Bethune HospitalShanxi Academy of Medical SciencesTaiyuan 030032China

Hyperplastic scar is a common fibrotic disease that may ultimately lead to severe dysfunction anddeformity,causing physical and psychological distress.Therefore,we aim to evaluate the effect of the mechanicalmicroenvironment of scar substrates on the morphology of human fibroblasts(HFbs).The micro-modular fabrication technique was used to design a new cross-groove topology and to construct four elastic substrates withthe stiffness of 19.3 kPa and 90.1 kPa coupled with parallel groove and cross groove,respectively,to simulate themechanical microenvironment of skin wounds and scar tissues.The morphological changes in HFbs in differentsubstrates were observed,and the changes in the cell-long axis length,area,and the angle between cell-long axisand grooves were recorded.Immunofluorescence staining was performed to observe the distribution of microfilaments.The results indicated that substrate stiffness and topography affected the morphology of HFbs.The cellswere elongated in parallel grooves as well as in the area where cross grooves restricted groove length,the celllength was restricted,and the angle between the long axis and the groove was increased.The topography exertedno significant effect on the cell area,but the cell area increased with increasing the stiffness.The parallel groovepromoted the expression of the F-actin to a certain extent,and the fluorescence intensity of F-actin decreased withincreasing the stiffness.Studying the effect of the mechanical microenvironment of substrates on HFb morphologyis of great importance for understanding the mechanisms of scar formation and prevention.

关键词： mechanical micro-environment matrix stiffness topological structure fibroblast

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Actin nucleator formins regulate the tension-buffering function of caveolin-1

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Journal of Molecular Cell Biology 2021年第12期13卷 876-888页

作者： Xuemeng Shi Daijiao Tang Yifan Xing Shuangshuang Zhao Changyuan Fan Jin Zhong Yanqin Cui Kun Shi Yaming Jiu The Joint Program in Infection and Immunity Guangzhou Women and Children’s Medical CenterGuangzhou Medical UniversityGuangzhou 510623China The Joint Program in Infection and Immunity Institut Pasteur of ShanghaiChinese Academy of SciencesShanghai 200031China Unit of Cell Biology and Imaging Study of Pathogen Host Interaction The Center for MicrobesDevelopment and HealthCAS Key Laboratory of Molecular Virology and ImmunologyInstitut Pasteur of ShanghaiChinese Academy of SciencesShanghai 200031China College of Life Sciences University of Chinese Academy of SciencesBeijing 100049China Unit of Viral Hepatitis CAS Key Laboratory of Molecular VirologyInstitut Pasteur of ShanghaiChinese Academy of SciencesShanghai 200031China

Both the mechanosensitive actin cytoskeleton and caveolae contribute to active processes such as cell migration,morphogenesis,and vesicular trafficking.Although distinct actin components are well studied,how they contribute to cytoplasmic caveolae,especially in the context of mechano-stress,has remained elusive.Here,we identify two actin-associated mobility stereotypes of caveolin-1(CAV-1)-marked intracellular vesicles,which are characterized as‘dwelling’and‘go and dwelling’.In order to exploit the reason for their distinct dynamics,elongated actin-associated formin functions are perturbed.We find drastically decreased density,increased clustering,and compromised motility of cytoplasmic CAV-1 vesicles resulting from lacking actin nucleator formins by both chemical treatment and RNA silencing of formin genes.Furthermore,hypo-osmosis-stimulated diminishing of CAV-1 is dramatically intensified upon blocking formins.The clustering of CAV-1 vesicles when cells are cultured on soft substrate is also aggravated under formin inhibition condition.Together,we reveal that actin-associated formins are essential for maintaining the dynamic organization of cytoplasmic CAV-1 and importantly its sensitivity upon mechanical challenge.We conclude that tension-controlled actin formins act as a safety valve dampening excessive tension on CAV-1 and safeguarding CAV-1 against mechanical damage.

关键词： caveolin-1 elongated actin filaments formins hypo-osmotic shock matrix stiffness

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Role of endothelial cells in the regulation of mechanical microenvironment on tumor progression

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Acta Mechanica Sinica 2021年第2期37卷 218-228页

作者： Changling Wei Mei Tang Zhiling Xu Li Yang Yonggang Lv Mechanobiology and Regenerative Medicine Laboratory Bioengineering CollegeChongqing UniversityChongqing 400044China Key Laboratory of Biorheological Science and Technology(Chongqing University) Ministry of EducationBioengineering CollegeChongqing UniversityChongqing 400044China

Majority of cancer patients die from cancer metastases.The physical stimulation produced by microenvironment regulates invasive behavior of cancer cells.Blood vessel is one of the“pathways”for cancer to metastasize,in which tumor cells need to cross the endothelial barrier for intravasation and extravasation.Tumor vessels are arranged in untraditional hierarchies and characterized with rupture,bend,swell and high permeability that are beneficial to intravasation of cancer cell.Abnormal vessels are accompanied with uneven blood flow,increased compression and interstitial fluid pressure.Meanwhile,excessive proliferation of tumor leads to low oxygen pressure in solid tumor.The aberrant tumor mechanical microenvironment changes the biochemical and mechanical signal transduction of endothelial cells and participates in tumor progression.Many current researches focus on how chemical signals regulate endothelial cell function while the role of physical cues is unclear.In this review,the role of endothelial cells in the regulation of shear stress,intercellular force,extracellular matrix and pressure on tumor progression is summarized.

关键词： Endothelial cells.Cancer metastases Mechanical microenvironment matrix stiffness Shear stress

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Three-dimensional decellularized tumor extracellular matrices with different stiffness as bioengineered tumor scaffolds

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Bioactive Materials 2021年第9期6卷 2767-2782页

作者： Yonggang Lv Hongjun Wang Gui Li Boyuan Zhao Mechanobiology and Regenerative Medicine Laboratory Bioengineering CollegeChongqing UniversityChongqing400044PR China Key Laboratory of Biorheological Science and Technology Chongqing UniversityMinistry of EducationBioengineering CollegeChongqing UniversityChongqing400044PR China

In the three-dimensional(3D)tumor microenvironment,matrix stiffness is associated with the regulation of tumor cells behaviors.In vitro tumor models with appropriate matrix stiffness are urgently desired.Herein,we prepare 3D decellularized extracellular matrix(DECM)scaffolds with different stiffness to mimic the microenvironment of human breast tumor tissue,especially the matrix stiffness,components and structure of ECM.Furthermore,the effects of matrix stiffness on the drug resistance of human breast cancer cells are explored with these developed scaffolds as case studies.Our results confirm that DECM scaffolds with diverse stiffness can be generated by tumor cells with different lysyl oxidase(LOX)expression levels,while the barely intact structure and major components of the ECM are maintained without cells.This versatile 3D tumor model with suitable stiffness can be used as a bioengineered tumor scaffold to investigate the role of the microenvironment in tumor progression and to screen drugs prior to clinical use to a certain extent.

关键词： Breast tumor cell Decellularized scaffold Lysyl oxidase Extracellular matrix matrix stiffness Drug resistance

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ANALYSIS OF STRESS CONCENTRATIONS IN UNIDIRECTIONAL COMPOSITES TAKING INTO ACCOUNT THE TENSILE LOAD IN THE matrix

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Acta Mechanica Solida Sinica 1998年第4期11卷 318-328页

作者： Ling, L Zeng, QD Guangdong Univ Technol Dept Mechatron Engn Guangzhou 510643 Peoples R China S China Univ Technol Dept Engn Mech Canton 510641 Peoples R China

A modified shear-lag model accounting for the effect of the tensile stiffness of the ma, trix is proposed for solving the stress redistribution due to the failure of fibers and matrix in unidirectionally fibre-reinforced composites. The advantages of this model are simple, reasonable and accurate by comparison with the other similar modified shear-lag models. It can be further extended to study the stress redistribution with interfacial damage between fibres and matrix This paper quantitatively dis cusses the influence of the tensile stiffness ratio of matrix to fibre and of the fibre volume fraction on the stress concentration in the fibres and ma trix adjacent to cut fibres and matrix, and suggests that the influence of the matrix stiffness on the stress concentration can be neglected when the matrix stiffness is low, such as polymer matrix composites, and the fibre volume fraction is high. For other cases such as ceramic and metal matrix composites, the tensile load of the matrix cannot be neglected in the shear-lag analysis.

关键词： unidirectional composites stress concentration matrix stiffness shear-lag analysis

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