Development of Sphingosine kinase (SPHK) inhibitors and the role of Sphingolipids in adult stem cell proliferation and differentiation

Abstract

In this study, six analogues of sphingosine were synthesized and evaluated as inhibitors for SPHKs. Some of them were proved to be more potent and specific to inhibit SPHK than other enzymes. One of the compounds (CP6), as well as N,N-dimethy-sphingosine (DMS), was shown to mediate the human mesenchymal stem cells (MSCs) differentiation. It was found that lower concentrations (0.5uM) of CP6 and DMS promoted human bone marrow- (BM-) and adipose derived- (AD-) MSCs osteogenic differentiation. However, higher concentration of CP6 (5uM) and DMS (1uM) showed to inhibit the osteogenic differentiation of the cells. In contrast, CP6 and DMS showed to promote the MSCs adipogenic differentiation in a dose-dependent manner. These findings suggest that SPHK might be potentially involved in stem cells osteogenic and adipogenic differentiation switching. Finally, Sphingosine-1-phosphate (S1P) was proved to mediate the MSCs proliferation when it worked with other growth factors.