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

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

朱鸿源^{1, 2,},
王与帅^{1, 2},
林敏^{1, 2, ,}

1.
西安交通大学生命科学与技术学院生物信息工程教育部重点实验室，西安 710049
2.
西安交通大学生物医学信息工程教育部重点实验室仿生工程与生物力学研究所(BEBC)，西安 710049

(我刊编委林敏来稿)

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)

中图分类号: O34;Q66
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- 文章访问数: 131
- HTML全文浏览量: 69
- PDF下载量: 26
- 被引次数: 0
出版历程
- 收稿日期: 2024-04-19
- 修回日期: 2024-05-06
- 刊出日期: 2024-06-01

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

ZHU Hongyuan^{1, 2
,},
WANG Yushuai^{1, 2},
LIN Min^{1, 2
, ,}

1.
The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P.R.China
2.
Bioinspired Engineering and Biomechanics Center (BEBC), The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an 710049, P.R.China

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

摘要

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.
- 力学模型 /
- 力-化耦合 /
- 上皮-间质转化 /
- 细胞间力学黏附
Abstract:
The epithelial-mesenchymal transition (EMT) is a critical step in physiological and pathological processes such as the embryonic development, the wound healing, and the cancer progression, wherein cells transition from a tightly adherent epithelial state to a dispersed mesenchymal state. An EMT core circuit model driven by the synergistic regulation of matrix stiffnesses and growth factors was proposed. The results show that, during the EMT, the matrix stiffnesses and growth factors collaboratively regulate the expression of the E/N-cadherin, a typical cell-cell adhesion molecule, by modulating the EMT-activating transcription factors, thus influencing the progression and reversibility of the EMT. The model elucidates the mechanism of synergistic interactions between mechanical and chemical factors on cell-cell adhesion during the EMT, laying a theoretical foundation for understanding the occurrence, development mechanisms, and preventive strategies against diseases such as cancer.
- mechanical modeling /
- mechanochemical coupling /
- epithelial-mesenchymal transition /
- cell-cell adhesion
edited-by

edited-by
注释:

1) (我刊编委林敏来稿)

HTML全文

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

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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

注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

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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

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图 4 在不同外源性TGF-β相对浓度(ρ_{TGF, 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(ρ_{TGF, 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 (ρ_{TGF, ext0}) for 10 days and then with indicated exogenous TGF-β levels (ρ_{TGF, ext1}) for another 10 days

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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

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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

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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

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图 8 上皮细胞在一定外源性TGF-β相对浓度(ρ_{TGF, 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 (ρ_{TGF, 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

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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

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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
ρ_{TGF, M}	relative expression of endogenous TGF-β in mesenchymal cells	10	[19]
ρ_{Rsnail, M}	relative expression of Snail mRNA in mesenchymal cells	5	[20, 43]
ρ_{SNAIL, M}	relative expression of SNAIL in mesenchymal cells	10	[20, 43]
ρ_{miR34, M}	relative expression of miR-34 in mesenchymal cells	0.15	[20]
ρ_{Rzeb, M}	relative expression of Zeb mRNA in mesenchymal cells	5	[20]
ρ_{ZEB, M}	relative expression of ZEB in mesenchymal cells	10	[20]
ρ_{miR200, M}	relative expression of miR-200 in mesenchymal cells	0.15	[20]
ρ_{Ecad, M}	relative expression of E-cadherin in mesenchymal cells	0.13	[20, 43]
ρ_{Ncad, 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
k_g^T/h^-1	production rate of TGF-β	0.25
J_T	Michaelis constant of miR-200-inhibited production of TGF-β	0.29
k_d^T/h^-1	degradation rate ofTGF-β	0.02
k_g0^s/h^-1	basic production rate of Snail mRNA	0.26
k_g^s/h^-1	TGF-β-dependent production rate of Snail mRNA	1.04
J_s	Michaelis constant of TGF-β-dependent Snail mRNA production	5
k_d^s/h^-1	degradation rate of Snail mRNA	0.26
k_g^S/h^-1	production rate of SNAIL	0.16
J_S	Michaelis constant of SNAIL production	1
k_d^S/h^-1	degradation rate of SNAIL	0.08
k_g³⁴/h^-1	production rate of miR-34	0.53
J_34S	Michaelis constant of SNAIL-dependent miR-34 production	10
J_34Z	Michaelis constant of ZEB-dependent miR-34 production	4.5
k_d³⁴/h^-1	degradation rate of miR-34	0.5
k_g^z/h^-1	production rate of Zeb mRNA	1.04
J_z	Michaelis constant of Zeb mRNA production	2
k_d^z/h^-1	degradation rate of Zeb mRNA	0.2
k_g^Z/h^-1	production rate ZEB	0.2
J_Z	Michaelis constant of ZEB production	1
k_d^Z/h^-1	degradation rate of ZEB	0.1
k_g²⁰⁰/h^-1	production rate of miR-200	0.53
J_200S	Michaelis constant of SNAIL-dependent miR-200 production	4.5
J_200Z	Michaelis constant of ZEB-dependent miR-200 production	10
k_d²⁰⁰/h^-1	degradation rate of miR-200	0.5
k_g1^E/h^-1	SNAIL-dependent production rate of E-cadherin	0.011
J_ES	Michaelis constant of SNAIL-dependent E-cadherin production	3.7
k_g2^E/h^-1	ZEB-dependent production rate of E-cadherin	0.011
J_EZ	Michaelis constant of ZEB-dependent E-cadherin production	3.7
k_d^E/h^-1	degradation rate of E-cadherin	0.02
k_g1^N/h^-1	SNAIL-dependent production rate of N-cadherin	0.086
J_NS	Michaelis constant of SNAIL-dependent N-cadherin production	2.76
k_g2^N/h^-1	ZEB-dependent production rate of N-cadherin	0.086
J_NZ	Michaelis constant of ZEB-dependent N-cadherin production	2.76
k_d^N/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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