This study investigates the influence of extracellular matrix (ECM) mechanics on the fate of mesenchymal stem cells (MSCs) in 3D micro-environments. The researchers found that MSC commitment to osteogenic lineage was significantly influenced by the rigidity of the 3D micro-environments, with optimal osteogenesis occurring at intermediate stiffness (11-30 kPa). This effect was not correlated with cell morphology but was linked to integrin binding and reorganization of adhesion ligands on the nanoscale, which were traction-dependent. The findings suggest that cells interpret changes in matrix stiffness as changes in adhesion ligand presentation, and that cell traction forces can be harnessed to mechanically process materials into structures that influence cell fate. The study also highlights the importance of synthetic ECM approaches for both basic research and medical applications, as they can provide more physiologically relevant conditions compared to traditional 2D culture systems.This study investigates the influence of extracellular matrix (ECM) mechanics on the fate of mesenchymal stem cells (MSCs) in 3D micro-environments. The researchers found that MSC commitment to osteogenic lineage was significantly influenced by the rigidity of the 3D micro-environments, with optimal osteogenesis occurring at intermediate stiffness (11-30 kPa). This effect was not correlated with cell morphology but was linked to integrin binding and reorganization of adhesion ligands on the nanoscale, which were traction-dependent. The findings suggest that cells interpret changes in matrix stiffness as changes in adhesion ligand presentation, and that cell traction forces can be harnessed to mechanically process materials into structures that influence cell fate. The study also highlights the importance of synthetic ECM approaches for both basic research and medical applications, as they can provide more physiologically relevant conditions compared to traditional 2D culture systems.