title: Bone marrow-derived mesenchymal stem cells differentiate to hepatic myofibroblasts by transforming growth factor-β1 via sphingosine kinase/sphingosine 1-phosphate (S1P)/S1P receptor axis.
abstract: Sphingosine kinase (SphK) is involved in numerous biological processes, including cell growth, proliferation, and differentiation. However, whether SphK participates in the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) to myofibroblasts has been unknown. In a carbon tetrachloride-treated mouse model, SphK1 was expressed in BMSCs in damaged liver. Furthermore, mRNA expression of both SphK1 and transforming growth factor β1 (TGF-β1) was significantly increased after liver injury, with a positive correlation between them. The SphK inhibitor SKI significantly blocked BMSC differentiation to myofibroblasts during liver injury (the proportion of BMSC-derived myofibroblasts decreased markedly, compared with no SKI treatment) and attenuated the extent of liver fibrosis. Using primary mouse BMSCs, we demonstrated that TGF-β1 induced BMSC differentiation to myofibroblasts, accompanied by the up-regulation of SphK1 and modulation of sphingosine 1-phosphate (S1P) receptor (S1PR) expression. Notably, pharmacological or siRNA-mediated inhibition of SphK1 abrogated the prodifferentiating effect of TGF-β1. Moreover, using either S1PR subtype-specific antagonists or specific siRNAs, we found that the prodifferentiating effect of TGF-β1 was mediated by S1PR(1) and S1PR(3). These data suggest that SphK1 activation by TGF-β1 leads to differentiation of BMSCs to myofibroblasts mediated by S1PR(1) and S1PR(3) up-regulation, thus providing new information on the mechanisms by which TGF-β1 gives rise to fibrosis and opening new perspectives for pharmacological treatment of liver fibrosis.
authors.affiliation: Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China.
authors.forename: Le
authors.initials: L
authors.lastname: Yang
authors.forename: Na
authors.initials: N
authors.lastname: Chang
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Han
authors.forename: Tieping
authors.initials: T
authors.lastname: Zhu
authors.forename: Changyong
authors.initials: C
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.forename: Liying
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D001853:Bone Marrow; D002251:Carbon Tetrachloride; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005677:G(M1) Ganglioside / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008813:Mice, Inbred ICR; D058628:Myofibroblasts / Q000473:pathology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D049349:Receptors, Lysosphingolipid / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D000099157:Sphingosine Kinase
chemical_list: D002251:Carbon Tetrachloride; D004791:Enzyme Inhibitors; D005677:G(M1) Ganglioside; D017853:Phosphotransferases (Alcohol Group Acceptor); D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; D053773:Transforming Growth Factor beta1; D000099157:Sphingosine Kinase