Mesenchymal stem cells attenuate liver fibrosis by suppressing Th17 cells – an experimental study

This study investigates molecular and cellular mechanisms involved in mesenchymal stem cell (MSCs)-mediated modulation of IL-17 signaling during liver fibrosis. Mice received CCl4 (1μL/g intraperitoneally) twice/week for 1 month. MSCs (1x106), or MSC-conditioned medium (MSC-CM) were intravenously injected 24h after CCl4 and on every 7th day. Liver fibrosis was determined by macroscopic examination, histological analysis, Sirius red staining and RT-PCR. Serum levels of cytokines, IDO and kynurenine were determined by ELISA. Flow cytometry was performed to identify liver infiltrated cells. In vitro, CD4+ T cells were stimulated and cultured with MSCs. 1-methyltryptophan was used for inhibition of Indoleamine 2,3-dioxygenase (IDO). MSCs significantly attenuated CCl4-induced liver fibrosis by decreasing serum levels of inflammatory IL-17, increasing immunosuppressive IL-10, IDO and kynurenine, reducing number of IL-17 producing Th17 cells and increasing percentage of CD4+IL-10+ T cells. Injection of MSC-CM resulted with attenuated fibrosis accompanied with the reduced number of Th17 cells in the liver, and decreased serum levels of IL-17. MSC-CM promoted expansion of CD4+FoxP3+IL-10+ T regulatory cells and suppressed proliferation of Th17 cells. This phenomenon was completely abrogated in the presence of IDO inhibitor. MSCs, in IDO dependent manner, suppress liver Th17 cells which lead to the attenuation of liver fibrosis. This article is protected by copyright. All rights reserved.