Sphingosine-l-phosphate/SIP Receptors Signaling Modulates Cell Migration in Human Bone Marrow-Derived Mesenchymal Stem Cells

摘要

The recruitment of bone marrow-derived mesenchymal stem cells (BMSCs) to damaged tissues and sites of inflammation is an essential step for clinical therapy. However, the signals regulating the motility of these cells are still not fully understood. Sphingosine-1-phosphate (SIP), a bioactive sphingolipid metabolite, is known to have a variety of biological effects on various cells. Here, we investigated the roles of SIP and SIP receptors (SIPRs) in migration of human BMSCs. We found that SIP exerted a powerful migratory action on human BMSCs. Moreover, by employing RNA interference technology and pharmacological tools, we demonstrated that S1PR1 and S1PR3 are responsible for SIP-induced migration of human BMSCs. In contrast, S1PR2 mediates the inhibition of migration. Additionally, we explored the downstream signaling pathway of the SIP/SlPRs axis and found that activation of S1PR1 or S1PR3 increased migration of human BMSCs through a Gf/extracellular regulated protein kinases 1/2-(ERK1/2-) dependent pathway, whereas activation of S1PR2 decreased migration through the Rho/Rho-associated protein kinase (ROCK) pathway. In conclusion, we reveal that the SIP/SlPRs signaling axis regulates the migration of human BMSCs via a dual-directional mechanism. Thus, selective modulation of SIPRs activity on human BMSCs may provide an effective approach to immunotherapy or tissue regeneration.