Mechanical regulation of cell volume in 3D extracellular matrices

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. (C) 2021 Elsevier Ltd. All rights reserved.