Most mammalian cells in the body live in a three-dimensional (3D) microenvironment. There is increasing evidence indicating that mechanical constraint from extracellular microenvironment exerts a crucial impact on cell volume regulation. The underlying mechanism of mechanical regulation for cell volume in 3D extracellular matrix (ECM), however, is not fully understood. Here, we developed a biomechanical model to investigate the interactions of cells with 3D ECM, which revealed a competitive relationship between intracellular cortices and 3D extracellular matrix (ECM) during volume adaption. We recognized that spatiotemporal dynamics of cell growth and volume adaption in 3D microenvironment was jointly regulated by initial cell size, ECM stiffness, interfacial prestress and tension of intracellular cortex layer, which was totally different from that in two-dimensional microenvironment. It was also demonstrated that, besides ECM rigidities, prestresses on cell–ECM interfaces played an equally critical role in constraining 3D cell growth. Additionally, we identified the geometric size-dependent sensitivity of cell volume variation in response to external stimuli, revealing a potential size effect during 3D cell growth. These findings not only quantitatively elucidate the key regulation of mechanical constraints from 3D ECM on cell volume adaption, but provide a fascinating insight into 3D cell–ECM interplays and resulting mechanosensing.

体内的大多数哺乳动物细胞都生活在三维 (3D) 微环境中。越来越多的证据表明来自细胞外微环境的机械约束对细胞体积调节产生了至关重要的影响。然而，3D 细胞外基质 (ECM) 中细胞体积的机械调节的潜在机制尚不完全清楚。在这里，我们开发了一个生物力学模型来研究细胞与 3D ECM 的相互作用，它揭示了在体积适应过程中细胞内皮质和 3D 细胞外基质 (ECM) 之间的竞争关系。我们认识到 3D 微环境中细胞生长和体积适应的时空动态受初始细胞大小、ECM 刚度、界面预应力和细胞内皮层张力共同调节，这与二维微环境中的完全不同。还证明，除了 ECM 刚性外，细胞-ECM 界面上的预应力在限制 3D 细胞生长方面也起着同样重要的作用。此外，我们确定了响应外部刺激的细胞体积变化的几何尺寸依赖性敏感性，揭示了 3D 细胞生长过程中的潜在尺寸效应。这些发现不仅定量地阐明了 3D ECM 对细胞体积适应的机械约束的关键调节，而且提供了对 3D 细胞-ECM 相互作用和由此产生的机械感应的迷人见解。我们确定了响应外部刺激的细胞体积变化的几何尺寸依赖性敏感性，揭示了 3D 细胞生长过程中的潜在尺寸效应。这些发现不仅定量地阐明了 3D ECM 对细胞体积适应的机械约束的关键调节，而且提供了对 3D 细胞-ECM 相互作用和由此产生的机械感应的迷人见解。我们确定了响应外部刺激的细胞体积变化的几何尺寸依赖性敏感性，揭示了 3D 细胞生长过程中的潜在尺寸效应。这些发现不仅定量地阐明了 3D ECM 对细胞体积适应的机械约束的关键调节，而且提供了对 3D 细胞-ECM 相互作用和由此产生的机械感应的迷人见解。