Hydrogel confinement of the secreted nascent matrix imposes solid stress and mediates pathology of chondrocytes

Mechanical confinement of cells in 3D hydrogel scaffolds mediates cell fate and activity across a wide range of biological processes. Many cells secrete a nascent matrix within the hydrogel niche, which provides important biological signals to the cells but also obstructs direct cell-hydrogel interactions, making it unclear how the cells sense hydrogel confinement and carry out mechanotransduction. Here, we show that chondrocytes sense the solid stress arising from the accumulation of the nascent matrix in the hydrogel niche, which is mediated by hydrogel viscoelasticity and plasticity. We show that solid stresses elicit a wide range of pathophysiological responses, most notably an inflammatory response associated with cartilage osteoarthritis and injury, alongside a striking progenitor-like migratory response where the chondrocytes leverage mitosis to breach their nascent matrix and migrate to escape confinement. Our findings establish the role of the nascent matrix as an important transducer of mechanical confinement and illustrate how emergent solid stresses can drive chondrocyte pathology.