Fluvastatin and lovastatin but not pravastatin induce neuroglial differentiation in human mesenchymal stem cells

Recent studies have shown that statins, the most potent inhibitors of 3-hydroxy-2-methylglutaryl coenzyme A (HMG-CoA) reductase, stimulate bone formation in vitro and in rodents by activating the expression of bone morphogenetic protein-2 (BMP-2), one of the most critical osteoblast differentiation-inducing factors. However, the effect of statins on mesenchymal stem cells (MSCs) is yet to be reported. The purpose of this study is to investigate the influence of fluvastatin, lovastatin, and pravastatin, three commonly prescribed lipid-lowering agents, on the proliferation and differentiation of human MSCs. To our surprise, even though fluvastatin and lovastatin effectively suppressed the growth of human MSCs, a neuroglia rather than osteoblast-like morphology was observed after treatment. Interestingly, such morphological change was inhibited by the co-addition of geranylgeranyl pyrophosphate (GGPP). Immunofluorescence staining with antibodies against neuron-, astrocyte-, as well as oligodendrocyte-specific markers confirmed the neuroglial identity of the differentiated cells. However, BMP-2 is unlikely to play a positive role in neuroglial differentiation of MSCs since its expression was down-regulated in fluvastatin-treated cells. Taken together, our results suggest that fluvastatin and lovastatin induce neuroglial differentiation of human MSCs and that these cholesterol-lowering agents might be used in conjunction with MSC transplantation in the future for treating neurological disorders and injuries.