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基质刚度和生长因子协同驱动上皮-间质转化的力-化耦合机制

朱鸿源 王与帅 林敏

朱鸿源, 王与帅, 林敏. 基质刚度和生长因子协同驱动上皮-间质转化的力-化耦合机制[J]. 应用数学和力学, 2024, 45(6): 719-734. doi: 10.21656/1000-0887.450107
引用本文: 朱鸿源, 王与帅, 林敏. 基质刚度和生长因子协同驱动上皮-间质转化的力-化耦合机制[J]. 应用数学和力学, 2024, 45(6): 719-734. doi: 10.21656/1000-0887.450107
ZHU Hongyuan, WANG Yushuai, LIN Min. The Mechanochemical Coupling Mechanism of Matrix Stiffnesses and Growth Factors Driving the Epithelial-Mesenchymal Transition[J]. Applied Mathematics and Mechanics, 2024, 45(6): 719-734. doi: 10.21656/1000-0887.450107
Citation: ZHU Hongyuan, WANG Yushuai, LIN Min. The Mechanochemical Coupling Mechanism of Matrix Stiffnesses and Growth Factors Driving the Epithelial-Mesenchymal Transition[J]. Applied Mathematics and Mechanics, 2024, 45(6): 719-734. doi: 10.21656/1000-0887.450107

基质刚度和生长因子协同驱动上皮-间质转化的力-化耦合机制

doi: 10.21656/1000-0887.450107
基金项目: 

国家自然科学基金 12202345

国家自然科学基金 12372316

中国博士后科学基金 2022M722534

中央高校基本科研业务费 xzy012024081

详细信息
    作者简介:

    朱鸿源(1992—),男,助理教授(E-mail: hongyuanzhu@xjtu.edu.cn)

    通讯作者:

    林敏(1982—),男,教授(通讯作者. E-mail: minlin@xjtu.edu.cn)

  • (我刊编委林敏来稿)
  • 中图分类号: O34;Q66

The Mechanochemical Coupling Mechanism of Matrix Stiffnesses and Growth Factors Driving the Epithelial-Mesenchymal Transition

  • (Contributed by LIN Min, M. AMM Editorial Board)
  • 摘要:

    上皮-间质转化(epithelial to mesenchymal transition, EMT)是胚胎发育、伤口愈合、癌症发展等生理、病理过程中的关键步骤,使细胞从紧密黏附在一起的上皮状态转变为分散排布的间质状态. 该文提出了一个基质刚度和生长因子协同驱动EMT的核心调控回路模型,发现在EMT过程中,基质刚度和生长因子通过协同调控EMT激活转录因子(EMT-activating transcript factors, EMT-TFs)来改变细胞间力学黏附分子E/N-钙黏素的表达,从而影响EMT的进程与可逆性. 该模型揭示了力学和化学因素的协同作用对EMT过程中细胞间力学黏附的影响机制,为研究癌症等疾病的发生、发展机制和防治策略奠定了理论基础.

    (Contributed by LIN Min, M. AMM Editorial Board)
    1)  (我刊编委林敏来稿)
  • 图  1  基质刚度和生长因子协同驱动EMT的核心调控回路模型

    Figure  1.  The EMT core circuit model driven by the synergistic regulation of the matrix stiffness and growth factors

    图  2  在高浓度外源性TGF-β和高基质刚度条件下,EMT过程中细胞的相关分子随时间的变化规律

      为了解释图中的颜色,读者可以参考本文的电子网页版本,后同.

    Figure  2.  Time evolutions of relative expressions of related molecules in cells during the EMT induced by the high exogenous TGF-β level and the high matrix stiffness

    图  3  不同外源性TGF-β相对浓度诱导10天后,已完全EMT的细胞中相关分子随时间的变化规律

    Figure  3.  The expressions of related molecules in cells treated with various exogenous TGF-β levels for 10 days

    图  4  在不同外源性TGF-β相对浓度(ρTGF, ext0)诱导细胞EMT发生10天后,将细胞置于相应外源性TGF-β相对浓度(ρTGF, ext1)下培养10天,细胞中钙黏素相对浓度的变化

    Figure  4.  Relative expressions of cadherins in cells firstly treated with various exogenous TGF-β levels (ρTGF, ext0) for 10 days and then with indicated exogenous TGF-β levels (ρTGF, ext1) for another 10 days

    图  5  外源性TGF-β诱导EMT的分岔分析

    Figure  5.  Bifurcations of EMT-related markers vs. the exogenous TGF-β level

    图  6  基质刚度与TWIST1核定位的关系

    Figure  6.  The relationship between the nuclear translocation of TWIST1 and the matrix stiffness

    图  7  有无外源性TGF-β刺激条件下,相关分子相对浓度随基质刚度的变化关系

    Figure  7.  Relative expressions of related molecules as a function of the matrix stiffness with or without exogenous TGF-β

    图  8  上皮细胞在一定外源性TGF-β相对浓度(ρTGF, ext0)培养10天后,再撤去外源性TGF-β培养10天,N-钙黏素相对浓度的最大值和最终值随不同外源性TGF-β相对浓度和基质刚度的变化相图

    Figure  8.  Phase diagrams showing N-cadherin maxima and end-point values at different matrix stiffnesses and exogenous TGF-β levels (ρTGF, ext0). The simulations correpond to epithetial cells firstly treated with various exogenous TGF-β levels for 10 days and then without exogenous TGF-β for another 10 days

    图  9  不同参数变化对N-钙黏素相对浓度的最大值和最终值的影响

    Figure  9.  The effects of changing parameters on N-cadherin maxima and end-point values

    表  1  完全EMT后细胞中相关分子的相对浓度

    Table  1.   Relative expressions of related molecules in the full EMT state

    notation meaning value reference
    ρTGF, M relative expression of endogenous TGF-β in mesenchymal cells 10 [19]
    ρRsnail, M relative expression of Snail mRNA in mesenchymal cells 5 [20, 43]
    ρSNAIL, M relative expression of SNAIL in mesenchymal cells 10 [20, 43]
    ρmiR34, M relative expression of miR-34 in mesenchymal cells 0.15 [20]
    ρRzeb, M relative expression of Zeb mRNA in mesenchymal cells 5 [20]
    ρZEB, M relative expression of ZEB in mesenchymal cells 10 [20]
    ρmiR200, M relative expression of miR-200 in mesenchymal cells 0.15 [20]
    ρEcad, M relative expression of E-cadherin in mesenchymal cells 0.13 [20, 43]
    ρNcad, M relative expression of N-cadherin in mesenchymal cells 8 [20, 43]
    下载: 导出CSV

    表  2  模型参数

    Table  2.   Parameters used in the model

    notation meaning value
    kgT/h-1 production rate of TGF-β 0.25
    JT Michaelis constant of miR-200-inhibited production of TGF-β 0.29
    kdT/h-1 degradation rate ofTGF-β 0.02
    kg0s/h-1 basic production rate of Snail mRNA 0.26
    kgs/h-1 TGF-β-dependent production rate of Snail mRNA 1.04
    Js Michaelis constant of TGF-β-dependent Snail mRNA production 5
    kds/h-1 degradation rate of Snail mRNA 0.26
    kgS/h-1 production rate of SNAIL 0.16
    JS Michaelis constant of SNAIL production 1
    kdS/h-1 degradation rate of SNAIL 0.08
    kg34/h-1 production rate of miR-34 0.53
    J34S Michaelis constant of SNAIL-dependent miR-34 production 10
    J34Z Michaelis constant of ZEB-dependent miR-34 production 4.5
    kd34/h-1 degradation rate of miR-34 0.5
    kgz/h-1 production rate of Zeb mRNA 1.04
    Jz Michaelis constant of Zeb mRNA production 2
    kdz/h-1 degradation rate of Zeb mRNA 0.2
    kgZ/h-1 production rate ZEB 0.2
    JZ Michaelis constant of ZEB production 1
    kdZ/h-1 degradation rate of ZEB 0.1
    kg200/h-1 production rate of miR-200 0.53
    J200S Michaelis constant of SNAIL-dependent miR-200 production 4.5
    J200Z Michaelis constant of ZEB-dependent miR-200 production 10
    kd200/h-1 degradation rate of miR-200 0.5
    kg1E/h-1 SNAIL-dependent production rate of E-cadherin 0.011
    JES Michaelis constant of SNAIL-dependent E-cadherin production 3.7
    kg2E/h-1 ZEB-dependent production rate of E-cadherin 0.011
    JEZ Michaelis constant of ZEB-dependent E-cadherin production 3.7
    kdE/h-1 degradation rate of E-cadherin 0.02
    kg1N/h-1 SNAIL-dependent production rate of N-cadherin 0.086
    JNS Michaelis constant of SNAIL-dependent N-cadherin production 2.76
    kg2N/h-1 ZEB-dependent production rate of N-cadherin 0.086
    JNZ Michaelis constant of ZEB-dependent N-cadherin production 2.76
    kdN/h-1 degradation rate of N-cadherin 0.02
    $\tilde{k}_{\mathrm{CN}}$ relative import rate of TWIST1 into nucleus 10
    $\tilde{k}_{\mathrm{g}}^{\mathrm{TG}}$ relative binding rate of TWIST1 to G3BP2 100
    E0/kPa stiffness where TWIST1 phosphorylation reaches the half maximum level 0.1
    下载: 导出CSV
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  • 收稿日期:  2024-04-19
  • 修回日期:  2024-05-06
  • 刊出日期:  2024-06-01

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