Abstract
Inflammation can induce cell senescence, which has been shown to decrease therapeutic effects of mesenchymal stem cells (MSCs). In this study, we intend to investigate the effects of inflammatory microenvironment on the biological functions and aging of MSCs and the mechanisms involved. Inflammatory serum was collected from endotoxemic rats and used to stimulate MSCs from healthy rat bone marrow MSCs (BMSCs). Morphology, proliferation, cell cycle and migration of BMSCs were detected. Our results showed that the inflammatory serum inhibited proliferation of BMSCs and induced an arrest of cell cycle, whereas the migratory capacity was increased. We then studied the senescence-associated phenotype in these cells. We showed that upon inflammatory serum stimulation, these BMSCs expressed high level of inflammatory cytokines as IL-6 and MCP1, and demonstrated high activity of SA-β-GAL. Moreover, they express high level of senescence-associated protein including P16 and P21. Furthermore, we showed that Notch signaling was involved in the inflammation induced BMSCs senescence. Notch1 and its downstream target Hes1 was upregulated upon inflammation stimulation in a time-dependent manner. Inhibition of Notch signaling could partially inhibit senescence associated changes in BMSCs. In conclusion, our results suggest that inflammatory microenvironment could induce BMSCs senescence through activation of Notch signaling.
Published Version
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