Mechanosensitive smooth muscle cell phenotypic plasticity emerging from a null state and the balance between Rac and Rho.
Mechanosensitive smooth muscle cell phenotypic plasticity emerging from a null state and the balance between Rac and Rho.
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DOI：
10.1016/j.celrep.2021.109019
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发表时间：
2021-04-20
期刊：
影响因子：
8.8
通讯作者：
Assoian RK
中科院分区：
文献类型：
--
作者：
Talwar S;Kant A;Xu T;Shenoy VB;Assoian RK
血管平滑肌细胞（VSMCs）的可逆分化在血管生物学和疾病中起着至关重要的作用。VSMC分化的变化与动脉细胞外基质（ECM）的硬度相关，但因果关系尚不清楚。我们发现，VSMC的可塑性是机械敏感的，去分化和分化的命运是由相同的ECM刚度促进。微分方程模型预测，一个空的VSMC状态产生的双重命运，在ECM刚度。细胞力，增殖和收缩基因表达的直接测量验证了这些预测，并表明命运的结果是由Rac-Rho稳态介导的。通过对雅普和TAZ的不同影响，Rac是两种命运所必需的。Rho单独驱动收缩状态，因此其相对于Rac的活性水平驱动表型选择。我们的研究结果表明，细胞对单一ECM刚度的反应如何产生双稳定性和VSMC可塑性。平滑肌细胞的可逆分化/去分化在血管生物学和疾病中起着关键作用。Talwar等人表明，这些分化和去分化表型来自于受ECM刚性和Rac对雅普和TAZ转录辅助调节因子的双向作用调节的无效状态。
Reversible differentiation of vascular smooth muscle cells (VSMCs) plays a critical role in vascular biology and disease. Changes in VSMC differentiation correlate with stiffness of the arterial extracellular matrix (ECM), but causal relationships remain unclear. We show that VSMC plasticity is mechanosensitive and that both the de-differentiated and differentiated fates are promoted by the same ECM stiffness. Differential equations developed to model this behavior predicted that a null VSMC state generates the dual fates in response to ECM stiffness. Direct measurements of cellular forces, proliferation, and contractile gene expression validated these predictions and showed that fate outcome is mediated by Rac-Rho homeostasis. Rac, through distinct effects on YAP and TAZ, is required for both fates. Rho drives the contractile state alone, so its level of activity, relative to Rac, drives phenotypic choice. Our results show how the cellular response to a single ECM stiffness generates bi-stability and VSMC plasticity. Reversible differentiation/de-differentiation of smooth muscle cells plays a critical role in vascular biology and disease. Talwar et al. show that these differentiated and de-differentiated phenotypes emerge from a null state that is regulated by ECM stiffness and bidirectional effects of Rac on YAP and TAZ transcriptional coregulators.
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影响因子：
64.8
作者：
Chang L;Azzolin L;Di Biagio D;Zanconato F;Battilana G;Lucon Xiccato R;Aragona M;Giulitti S;Panciera T;Gandin A;Sigismondo G;Krijgsveld J;Fassan M;Brusatin G;Cordenonsi M;Piccolo S
通讯作者：
Piccolo S
DOI：
10.1038/nrm2890
发表时间：
2010-05
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1161/atvbaha.110.221135
发表时间：
2011-07
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Mack CP
通讯作者：
Mack CP
影响因子：
19
作者：
Guilluy C;Garcia-Mata R;Burridge K
通讯作者：
Burridge K
影响因子：
9.3
作者：
Byrne KM;Monsefi N;Dawson JC;Degasperi A;Bukowski-Wills JC;Volinsky N;Dobrzyński M;Birtwistle MR;Tsyganov MA;Kiyatkin A;Kida K;Finch AJ;Carragher NO;Kolch W;Nguyen LK;von Kriegsheim A;Kholodenko BN
通讯作者：
Kholodenko BN