gamma-Secretase inhibitor reverts the Notch signaling attenuation of osteogenic differentiation in aged bone marrow mesenchymal stem cells

摘要

The age-related changes in cell viability and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) play pivotal roles in the fracture healing process, especially in geriatric individuals. This study was designed to explore the age-related changes in murine BMSCs and the regulation of osteogenic differentiation in aged BMSCs in vitro. Notch signaling pathway took part in the regulation of osteogensis, while the relationship between Notch and the osteogenic differentiation in aged BMSCs has not been reported yet. BMSCs harvested from the bone marrow of young, adult, and aged C57BL/6 mice were cultured in osteogenic and adipogenic differentiation media. Histochemical staining results indicated that the osteogenic ability of BMSCs gradually decreased with aging, whereas the adipogenic ability increased. Cell activity assays showed that the proliferative and migrated capacity did not decline with aging significantly. According to real-time PCR and Western blotting results, the aged cells exhibited higher Notch signaling expression level than the younger ones did. After the aged BMSCs being treated with -secretase inhibitor, however, Notch activity was changed and the aging-imparied osteogenic ability reverted to a normal level. This study demonstrated that the decreased bone formation capacity in aged BMSCs had relationship with the transdifferentiation between osteogenesis and adipogenesis, which would be regulated by Notch signaling pathway and the attenuated osteogenesis in aged BMSCs could be promoted when the inhibition of Notch pathway.