期刊
BIOACTIVE MATERIALS
卷 18, 期 -, 页码 492-506出版社
KEAI PUBLISHING LTD
DOI: 10.1016/j.bioactmat.2022.03.036
关键词
Osteogenesis; Osteoporosis; Extracellular matrix; Stiffness; PCK2; Mesenchymal stem cells
资金
- National Natural Science Foundation of China [81870742, 81970911]
- Beijing Natural Science Foundation [7202233]
- Key Project of the National Natural Science Foundation of China [81930026]
- China Postdoctoral Science Foundation [2020TQ0020, 2021M700280]
- Research Foundation of Peking University School and Hospital of Stomatology [PKUSS20210102]
This study reveals the role of extracellular matrix stiffness in regulating stem cell fate and the novel mechanism of mitochondrial phosphoenolpyruvate carboxykinase in promoting osteogenesis in 3D matrix. These findings provide new perspectives for strategies of osteoporosis.
Understanding mechanisms underlying the heterogeneity of multipotent stem cells offers invaluable insights into biogenesis and tissue development. Extracellular matrix (ECM) stiffness has been acknowledged as a crucial factor regulating stem cell fate. However, how cells sense stiffness cues and adapt their metabolism activity is still unknown. Here we report the novel role of mitochondrial phosphoenolpyruvate carboxykinase (PCK2) in enhancing osteogenesis in 3D ECM via glycolysis. We experimentally mimicked the physical characteristics of 3D trabeculae network of normal and osteoporotic bone with different microstructure and stiffness, observing that PCK2 promotes osteogenesis in 3D ECM with tunable stiffness in vitro and in vivo. Mechanistically, PCK2 enhances the rate-limiting metabolic enzyme pallet isoform phosphofructokinase (PFKP) in 3D ECM, and further activates AKT/extracellular signal-regulated kinase 1/2 (ERK1/2) cascades, which directly regulates osteogenic differentiation of MSCs. Collectively, our findings implicate an intricate crosstalk between cell mechanics and metabolism, and provide new perspectives for strategies of osteoporosis.
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