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.     

Soyasaponin I decreases the expression of alpha2,3-linked sialic acid on the cell surface and suppresses the metastatic potential of B16F10 melanoma cells

The transfer of sialic acids to the non-reducing terminal positions on sugar chains of glycoconjugates is catalyzed by sialyltransferases (STs). Increased sialylation is correlated with oncogenic transformation and metastatic potential. ST inhibitors may be potentially valuable as anti-cancer and anti-metastatic agents. In this study, we evaluated the effects of soyasaponin I (Ssa I), a known inhibitor of STs, on tumor metastasis through studying a highly metastatic cancer cell line B16F10. Ssa I specifically inhibited the expression of alpha2,3-linked sialic acids without affecting other glycans on the B16F10 cell surface. We also found that Ssa I decreased the migratory ability of cells, enhanced cell adhesion to extracellular matrix proteins. Finally, a pulmonary metastasis assay demonstrated that alteration of glycosylation in this way significantly reduced the ability of tumor cells to distribute to the lungs of mice. Collectively, these findings suggested that alpha2,3-linked sialic acids may play an important role in metastasis potential of B16F10 cells.     

Lung defects in neonatal and adult stromal-derived factor–1 conditional knockout mice

Stromal-derived factor (SDF)-1/CXCL12 is a cytokine that is involved in organogenesis, hematopoiesis, chemoattraction, and wound healing. An SDF-1 knockout mouse (SDF-1^-/-) has provided important insights into the role of SDF-1 in fetal development. Because the SDF-1 knockout is lethal in the perinatal period, we have created a conditional SDF-1 knockout mouse. In the present study, we induced conditionally knocked out SDF-1 in neonatal mice and found that lung development was compromised; neonatal lungs showed increased alveolar airspace and abnormal ultrastructure. Conditional knockout of SDF-1 in adult mice resulted in an emphysemic morphology, with increased alveolar airspace and thickened alveolar septa. Fluorescence angiography showed pulmonary vessel hyperdilation. To determine whether the hyperdilation involved nitric oxide, we inhibited endothelial nitric oxide synthase (eNOS) with N (G)-nitro-L- arginine methyl ester. This resulted in the inhibition of pulmonary vessel hyperdilation. Western blot results showed increased phosphorylation of eNOS in our induced SDF-1 knockout mice, indicating that eNOS is normally repressed in the presence of SDF-1, and that activation of eNOS contributes to pulmonary pathology. Thus, a conditional knockout mouse has been successsfully created for SDF-1; initial characterization indicates that SDF-1 is intimately involved in lung development and physiology.