Enhanced apoptosis and senescence of bone-marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus

Abstract

Previous studies indicated that bone marrow mesenchymal stem cells (BMSCs) from patients with systemic lupus erythematosus (SLE) exhibited impaired capacities of proliferation, differentiation, secretion of cytokines, and immune modulation. In this study, we aimed to investigate whether apoptosis and senescence of SLE BMSCs were dysregulated. We found that there were increased frequencies of apoptotic and aging SLE BMSCs in comparison with those of normal controls. Notably, levels of Bcl-2 expression in SLE BMSCs were markedly decreased both at mRNA and protein levels. When BMSCs were induced to apoptosis by tumor necrosis factor-α (TNF-α) stimulation in vitro, the Bax and caspase 8 expression in SLE BMSCs was significantly increased at mRNA levels. The activity of caspase 8 was also enhanced in SLE BMSCs. More cytochrome-C-positive pellets in the cytosolic fraction of BMSCs were detected in SLE patients than in normal controls. The expression of Fas and tumor necrosis factor-α receptor 1 in SLE BMSCs was significantly upregulated compared with normal controls, and the serum levels of FasL and TNF-α were also elevated. Moreover, intracellular reactive oxygen species levels of SLE BMSCs were higher than those of normal controls, with the activation of PI3K/AKT/FoxO3 signaling pathway. Taken together, our results demonstrate increased apoptosis and senescence in SLE BMSCs, which may be associated with the pathogenesis of SLE.