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FTY720, a Sphingosine-1 Phosphate Receptor Modulator, Improves Liver Fibrosis in a Mouse Model by Impairing the Motility of Bone Marrow-Derived Mesenchymal Stem Cells

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Abstract

FTY720 is a novel immunosuppressant that modulates sphingosine 1-phosphate (S1P) receptors for the treatment of several diseases. Several hallmarks of liver fibrosis are influenced by S1P, and the interference of S1P signaling by treatment with FTY720 results in beneficial effects in various animal models of fibrosis. However, whether these treatment strategies suppress liver fibrosis progression is incompletely understood. Here, we investigated the effects and mechanisms by which FTY720 improves liver fibrosis in the carbon tetrachloride (CCl4)-induced mouse model. FTY720 treatment significantly attenuated the expression of fibrotic markers in the injured liver of both wild-type and SCID-beige mice. The migration of bone marrow-derived mesenchymal stem cells (BMSCs) to circulation, and subsequently the injured liver, was suppressed by FTY720. Furthermore, in vitro, phosphorylated-FTY720 blocked the migration of BMSCs mediated by S1P. Thus, FTY720 is an effective therapy for liver fibrosis via the suppression of BMSC migration in the CCl4-induced mouse model.

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Acknowledgments

We thank Professor Lingsong Li for his scientific advice. This work was supported through the Grants 863 Program (2009DFB30300) from the Ministry of Science and Technology of China.

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Authors and Affiliations

  1. Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China

    Yaxian Kong

  2. Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China

    Yaxian Kong

  3. Stem Cell Research Center, Peking University, Beijing, 100191, China

    Hong Wang, Shuling Wang & Na Tang

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Correspondence to Yaxian Kong.

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Supplementary Fig. 1

Absolute number of circulating BMSCs during liver fibrogenesis. Mice were induced by CCl4 administration for 4 weeks, with or without FTY720 treatment. The number of circulating BMSCs at different time points after OO or CCl4 injection, with or without FTY720 treatment. Data are presented as the mean ± SEM. *P < 0.05 vs. CCl4-treated alone (n = 16 per group). (JPEG 643 kb)

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Kong, Y., Wang, H., Wang, S. et al. FTY720, a Sphingosine-1 Phosphate Receptor Modulator, Improves Liver Fibrosis in a Mouse Model by Impairing the Motility of Bone Marrow-Derived Mesenchymal Stem Cells. Inflammation 37, 1326–1336 (2014). https://doi.org/10.1007/s10753-014-9877-2

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