Heterogeneous role of integrins in fibroblast response to small cyclic mechanical stimulus generated by a nanoporous gold actuator
Heterogeneous role of integrins in fibroblast response to small cyclic mechanical stimulus generated by a nanoporous gold actuator
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DOI：
10.1016/j.actbio.2020.12.014
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发表时间：
2021-01-27
影响因子：
9.7
通讯作者：
Mabuchi, Mamoru
中科院分区：
文献类型：
--
作者：
Deguchi, Soichiro;Kato, Atsushi;Mabuchi, Mamoru
了解机械刺激对细胞行为的影响对维持细胞内环境稳定具有重要意义。虽然细胞对机械刺激的响应已经有了很多研究，但其机械感知机制仍存在争议。在本研究中，实验采用分子动力学（MD）模拟循环机械刺激对细胞增殖的影响进行的基础上的假设，mechanosensing依赖于整合素类型。我们使用纳米多孔金（NPG）致动器，以防止通过分子以外的整合素的机械刺激的转移。令人惊讶的是，仅0.5%的小循环应变增强了成纤维细胞的增殖。α（5）β（1）和α v β 3整联蛋白显示出对机械刺激的高敏感性，而α（1）β（1）和α（2）β（1）整联蛋白显示出低的机械敏感性。MD模拟表明，不同的构象变化的整合素头部诱导的结合到ECM导致机械敏感性之间的差异α I和α I-少整合素类型。因此，本研究提供了证据来支持这一假设，并提出了机制的异质性的整合素在mechanosensing.Statement的significanceThe新颖性，目前的新奇是澄清的机制，整合素的mechanosensitivity大大改变取决于α I结构域的存在或不存在。我们使用纳米多孔金致动器在没有支架的细胞上加载循环刺激。实验表明，仅0.5%的小循环应变增强成纤维细胞的增殖，并且α（5）β（1）/α（v）β（3）整联蛋白显示出高的机械敏感性，而α（1），β（1）/α（2）β（1）整联蛋白显示出低的机械敏感性。我们还进行了MD模拟，以揭示为什么机械传感取决于整合素类型，重点是整合素头端开口。模拟阐明了一个微妙的结构变化的α I-少整合素最终导致一个戏剧性的头部开放的机制。(c)2020 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
It is important to understand the effects of mechanical stimulation on cell behaviors for homeostasis. Many studies have been performed on cell responses to mechanical stimuli, but the mechanosensing mechanism is still under debate. In the present study, experiments employing molecular dynamics (MD) simulations concerning the effects of cyclic mechanical stimulus on cell proliferation were performed based on the hypothesis that mechanosensing depends on integrin types. We used a nanoporous gold (NPG) actuator to prevent transfer of a mechanical stimulus via molecules other than integrins. Surprisingly, a small cyclic strain of only 0.5% enhanced the proliferation of fibroblasts. alpha(5)beta(1) and alpha v,63 integrins showed high sensitivity to the mechanical stimulus, whereas alpha(1)beta(1) and alpha(2)beta(1) integrins exhibited low mechanosensitivity. The MD simulations showed that different conformational changes of the integrin headpiece induced by binding to the ECM led to a difference in mechanosensitivity between alpha I and alpha I-less integrin types. Thus, the present study provides evidence to support the hypothesis and suggests the mechanism for the heterogeneous roles of integrins in mechanosensing.Statement of significanceThe novelty of the present work is to clarify the mechanism by which the mechanosensitivity of integrin is greatly changed depending on the presence or absence of alpha I domain. We used a nanoporous gold actuator to load a cyclic stimulus on cells without a scaffold. The experiments showed that a small cyclic strain of only 0.5% enhanced the proliferation of fibroblasts, and that alpha(5)beta(1)/alpha(v)beta(3) integrins showed high mechanosensitivity whereas alpha(1),beta(1)/alpha(2)beta(1) integrins exhibited low mechanosensitivity. We also performed MD simulations to disclose why the mechanosensing depended on the integrin types, focusing on the integrin headpiece opening. The simulations elucidated the mechanism by which a subtle structural change in the alpha I-less integrin eventually leads to a dramatic headpiece opening.(c) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.