This study investigates how the degradation of covalently crosslinked hyaluronic acid (HA) hydrogels influences the differentiation of human mesenchymal stem cells (hMSCs). The research shows that hMSCs in HA hydrogels with higher degradation rates exhibit more cell spreading and traction, favoring osteogenesis, while those in less degradable hydrogels show less spreading and traction, favoring adipogenesis. This suggests that cell-mediated degradation of the hydrogel matrix is a key factor in directing stem cell fate, independent of cell morphology or matrix stiffness. The study also demonstrates that inhibiting tension-mediated signaling in a permissive hydrogel environment mimics the effects of delayed secondary crosslinking, which reduces hydrogel degradation and suppresses traction, leading to a shift from osteogenesis to adipogenesis. Conversely, upregulating tension in a restrictive environment promotes osteogenesis. The research highlights the importance of hydrogel structure and behavior in modulating stem cell fate. It shows that the type of hydrogel (covalently crosslinked HA versus ionically crosslinked alginate) and its dimensionality (3D versus 2D) significantly influence stem cell adhesion and differentiation. The study also reveals that the ability of cells to degrade and interact with the hydrogel during differentiation determines their fate, regardless of whether the cells are spread or rounded. The findings indicate that traction generation through cell-mediated degradation is crucial for directing stem cell fate in 3D hydrogels. The study further shows that the introduction of non-degradable crosslinks after cell spreading prevents further matrix deformation, and that the type of hydrogel used can significantly impact stem cell behavior and fate. Overall, the study provides new insights into the role of traction generation in stem cell fate choice within 3D hydrogels. It emphasizes the importance of understanding stem cell interactions with different hydrogel types, as their degradability and molecular structure can drive divergent outcomes, impacting the design of hydrogels for stem cell-based therapies.This study investigates how the degradation of covalently crosslinked hyaluronic acid (HA) hydrogels influences the differentiation of human mesenchymal stem cells (hMSCs). The research shows that hMSCs in HA hydrogels with higher degradation rates exhibit more cell spreading and traction, favoring osteogenesis, while those in less degradable hydrogels show less spreading and traction, favoring adipogenesis. This suggests that cell-mediated degradation of the hydrogel matrix is a key factor in directing stem cell fate, independent of cell morphology or matrix stiffness. The study also demonstrates that inhibiting tension-mediated signaling in a permissive hydrogel environment mimics the effects of delayed secondary crosslinking, which reduces hydrogel degradation and suppresses traction, leading to a shift from osteogenesis to adipogenesis. Conversely, upregulating tension in a restrictive environment promotes osteogenesis. The research highlights the importance of hydrogel structure and behavior in modulating stem cell fate. It shows that the type of hydrogel (covalently crosslinked HA versus ionically crosslinked alginate) and its dimensionality (3D versus 2D) significantly influence stem cell adhesion and differentiation. The study also reveals that the ability of cells to degrade and interact with the hydrogel during differentiation determines their fate, regardless of whether the cells are spread or rounded. The findings indicate that traction generation through cell-mediated degradation is crucial for directing stem cell fate in 3D hydrogels. The study further shows that the introduction of non-degradable crosslinks after cell spreading prevents further matrix deformation, and that the type of hydrogel used can significantly impact stem cell behavior and fate. Overall, the study provides new insights into the role of traction generation in stem cell fate choice within 3D hydrogels. It emphasizes the importance of understanding stem cell interactions with different hydrogel types, as their degradability and molecular structure can drive divergent outcomes, impacting the design of hydrogels for stem cell-based therapies.