Extracellular matrix stiffness as an energy metabolism regulator drives osteogenic differentiation in mesenchymal stem cells.

The biophysical factors of biomaterials such as their stiffness regulate stem cell differentiation. Energy metabolism has been revealed an essential role in stem cell lineage commitment. However, whether and how extracellular matrix (ECM) stiffness regulates energy metabolism to determine stem cell differentiation is less known. Here, the study reveals that stiff ECM promotes glycolysis, oxidative phosphorylation, and enhances antioxidant defense system during osteogenic differentiation in MSCs. Stiff ECM increases mitochondrial fusion by enhancing mitofusin 1 and 2 expression and inhibiting the dynamin-related protein 1 activity, which contributes to osteogenesis. Yes-associated protein (YAP) impacts glycolysis, glutamine metabolism, mitochondrial dynamics, and mitochondrial biosynthesis to regulate stiffness-mediated osteogenic differentiation. Furthermore, glycolysis in turn regulates YAP activity through the cytoskeletal tension-mediated deformation of nuclei. Overall, our findings suggest that YAP is an important mechanotransducer to integrate ECM mechanical cues and energy metabolic signaling to affect the fate of MSCs. This offers valuable guidance to improve the scaffold design for bone tissue engineering constructs.