Membrane voltage (Vm) plays a critical role in the regulation of several cellular behaviors, including proliferation, apoptosis and phenotypic plasticity. Many of these behaviors are affected by the stiffness of the underlying extracellular matrix, but the connections between Vm and the mechanical properties of the microenvironment are unclear. Here, we investigated the relationship between matrix stiffness and Vm by culturing mammary epithelial cells on synthetic substrata, the stiffnesses of which mimicked those of the normal mammary gland and breast tumors. Although proliferation is associated with depolarization, we surprisingly observed that cells are hyperpolarized when cultured on stiff substrata, a microenvironmental condition that enhances proliferation. Accordingly, we found that Vm becomes depolarized as stiffness decreases, in a manner dependent on intracellular Ca2+. Furthermore, inhibiting Ca2+-gated Cl- currents attenuates the effects of substratum stiffness on Vm. Specifically, we uncovered a role for cystic fibrosis transmembrane conductance regulator (CFTR) in the regulation of Vm by substratum stiffness. Taken together, these results suggest a novel role for CFTR and membrane voltage in the response of mammary epithelial cells to their mechanical microenvironment.

中文翻译：

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基质硬度调节乳腺上皮细胞的膜电压。

膜电压 (Vm) 在多种细胞行为的调节中发挥着关键作用，包括增殖、凋亡和表型可塑性。其中许多行为都受到底层细胞外基质刚度的影响，但 Vm 与微环境机械性能之间的联系尚不清楚。在这里，我们通过在合成基质上培养乳腺上皮细胞来研究基质硬度和 Vm 之间的关系，其硬度模仿正常乳腺和乳腺肿瘤的硬度。尽管增殖与去极化相关，但我们令人惊讶地观察到，当细胞在坚硬的基质上培养时会发生超极化，这是一种增强增殖的微环境条件。因此，我们发现随着刚度降低，Vm 会去极化，其方式取决于细胞内 Ca2+。此外，抑制 Ca2+ 门控 Cl- 电流可减弱基质硬度对 Vm 的影响。具体来说，我们发现了囊性纤维化跨膜电导调节器（CFTR）在通过基质硬度调节 Vm 中的作用。综上所述，这些结果表明 CFTR 和膜电压在乳腺上皮细胞对其机械微环境的响应中发挥着新的作用。