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

• Published in: Bioactive materials Vol. 35; pp. 549 - 563
• Main Authors: Na, Jing, Yang, Zhijie, Shi, Qiusheng, Li, Chiyu, Liu, Yu, Song, Yaxin, Li, Xinyang, Zheng, Lisha, Fan, Yubo
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.05.2024; KeAi Publishing Communications Ltd; KeAi Publishing; KeAi Communications Co., Ltd
• Subjects: Biomaterials; Biomedical materials; Biosynthesis; Cell differentiation; Cell growth; Cell lineage; Cellular mechanics; Cytoskeleton; Dehydrogenases; Differentiation (biology); Dynamin; Energy; Energy metabolism; Extracellular matrix; Fatty acids; Glucose; Glutamine; Glycolysis; Kinases; Matrix stiffness; Mesenchymal stem cells; Metabolic engineering; Metabolic regulation; Metabolism; Metabolites; Mitochondria; Osteogenesis; Oxidative metabolism; Oxidative phosphorylation; Phosphorylation; Protein turnover; Proteins; Stem cell fate; Stem cells; Stiffness; Tissue engineering; YAP; Yes-associated protein; United Kingdom > UK; Metabolic regulation; YAP; Cellular mechanics; Stem cell fate; Matrix stiffness
• ISSN: 2452-199X; 2097-1192; 2452-199X
• DOI: 10.1016/j.bioactmat.2024.02.003

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. [Display omitted] •Glycolysis is the main source of ATP for ECM stiffness-induced osteogenic differentiation in MSCs.•Stiff ECM promotes mitochondrial fusion and biosynthesis.•YAP acts as a mechan-matabolic sensor to regulate osteogenic capacity of MSCs.•ECM stiffness-induced glycolysis regulates YAP via cellular mechanics.