Background Mesenchymal stem cells (MSC) derived from patients with systemic lupus erythematosus (SLE) displays enhanced senescence.
Objectives The aim is to explore the role and mechanism of SLE inflammatory environment on the regulation of MSC senescence.
Methods Mesenchymal stem cells were isolated from fresh umbilical cords or human bone marrow. Cellular senescence was measured by senescence-associated b-galactosidase (SA-b-gal) staining, and the mRNA and protein levels of cell cycle inhibitors p53 and p21 were detected by real time PCR and western blot analysis. Proteins involved in senescence related signaling pathways, including Jak/stat, Ras/MEK/Erk, NF-kB and PI3K/Akt, were detected by western blot. Human serum collected from healthy controls and SLE patients were applied for the measurement of 80 human cytokines and chemokines by RayBio® human cytokine antibody arrays. Then differentially expressed factors were replicated by ELISA using independent samples.
Results SLE serum significantly increased the percentage of SA-b-gal positive MSCs, and upregulated the expression of p53 and p21. Jak/stat1/5, PI3K/Akt and MEK/Erk pathways in MSCs were activated after SLE serum stimulation. Treatment of PI3K/Akt signaling pathway inhibitor, LY294002, could reverse SLE serum induced senescence, while blocking Jak/stat with AG490 or MEK/Erk with PD98059 did not have an effect. As detected by cytokine antibody arrays and independent sample ELISA, leptin and NAP2 were both significantly elevated in SLE serum, and blocking either of them could partially inhibit MSC senescence. Leptin and NAP2 acted synergistically to promote more senescent cells than leptin or NAP2 alone, which were completely blocked by the PI3K/Akt pathway inhibitor.
Conclusions Elevation of leptin and NAP2 in SLE serum helps to accelerate the cellular senescence of MSCs. PI3K/Akt signaling transduction is important in the senescent effect.
Disclosure of Interest : None declared
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