3D confinement physically regulates cell cycle progression in budding yeast

Our understanding of cell division control traditionally comes via using liquid broths or 2D flat-plate cultures - which cannot recapitulate the complex visco-elasto-plastic properties of natural habitats such as tissues, mucus, and soil. Consequently, how such regimes of physical confinement influence proliferative growth remains poorly understood. Here, using engineered, mechanically tunable and transparent growth matrices, we directly visualize yeast budding and division across 3D viscoelastic regimes. We discover that elevated physical confinement drastically prolongs budding intervals without any physiological defects or activating global regulatory programs. Remarkably, extended cell division times are not associated with transcriptional or proteomic signatures of mechanosensation or cell cycle regulation. Rather, 3D confinement physically constrains the volumetric growth of incipient buds - manifesting as delayed cell cycle progression. Hence, our findings establish that physical constrainment regulates eukaryotic cell division. The eukaryotic cell cycle is highly responsive to genetic, metabolic, and biochemical regulation. But how do the mechanics of complex natural environments influence this fundamental process? This study shows that 3D confinement physically slows down cell division by constraining volumetric growth.