Adipose tissue‐derived stem cells prevent fibrosis in murine steatohepatitis by suppressing IL‐17‐mediated inflammation

• Published in: Journal of gastroenterology and hepatology Vol. 34; no. 8; pp. 1432 - 1440
• Main Authors: Yamato, Masatoshi, Sakai, Yoshio, Mochida, Hatsune, Kawaguchi, Kazunori, Takamura, Masayuki, Usui, Soichiro, Seki, Akihiro, Mizukoshi, Eishiro, Yamashita, Taro, Yamashita, Tatsuya, Ishida, Kousuke, Nasti, Alessandro, Tuyen, Ho Thuy Bich, Komura, Takuya, Yoshida, Keiko, Wada, Takashi, Honda, Masao, Kaneko, Shuichi
• Format: Journal Article
• Language: English
• Published: Australia Wiley Subscription Services, Inc 01-08-2019
• Subjects: Adipose tissue; Adipose Tissue - cytology; Adipose Tissue - transplantation; adipose‐tissue‐derived stromal/stem cells; Animals; Cell culture; Cell Line; Cell Proliferation; Coculture Techniques; Diet, High-Fat; Disease Progression; DNA microarrays; Fatty liver; Female; Fibrosis; Gene expression; hepatic inflammatory cell; Hepatic Stellate Cells - immunology; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; High fat diet; Inflammation; Inflammation Mediators - immunology; Inflammation Mediators - metabolism; Interleukin-17 - immunology; Interleukin-17 - metabolism; Interleukin-17 - pharmacology; interleukin‐17; Liver; Liver - immunology; Liver - metabolism; Liver - pathology; Liver Cirrhosis, Experimental - immunology; Liver Cirrhosis, Experimental - metabolism; Liver Cirrhosis, Experimental - pathology; Liver Cirrhosis, Experimental - prevention & control; Lymphoid cells; Mice, Inbred C57BL; NASH; Non-alcoholic Fatty Liver Disease - immunology; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Non-alcoholic Fatty Liver Disease - prevention & control; Spleen; Steatosis; stellate cell; Stem Cell Transplantation; Stem cells; Stem Cells - drug effects; Stem Cells - metabolism; interleukin-17; hepatic inflammatory cell; adipose-tissue-derived stromal/stem cells; stellate cell; NASH
• ISSN: 0815-9319; 1440-1746
• DOI: 10.1111/jgh.14647

Background and Aim
The pathological features of non‐alcoholic steatohepatitis (NASH) have not been determined, so fundamental treatment has not been established. Adipose‐tissue‐derived stromal/stem cells (ADSCs) are beneficial for repair/regenerative therapy of impaired organs because of their immuno‐modulatory capability. In this study, we assessed how liver damage progresses during the early development phase of the murine NASH model and investigated whether ADSCs are preventatively efficacious against the fibrosis progression of NASH.
Methods
C57BL/6J mice were fed with atherogenic high fat or high‐fat diet 60 developing into NASH or simple steatosis. Their hepatic inflammatory cells (HICs) were analyzed by cDNA microarray. NASH mice were treated with ADSCs injected into spleen when hepatic inflammation was initially observed, and liver samples were analyzed. The effect of ADSCs on the mice hepatic stellate cell (HSC) line stimulated by recombinant IL‐17 and HICs from NASH mice was analyzed.
Results
The gene expression features of HICs implicated as humoral cytokine mediators of lymphoid cells during NASH development, compared with a simple steatosis model. One of the featured cytokines was IL‐17. The development of hepatic fibrosis was alleviated when NASH mice were treated with ADSCs as well as treated with anti‐IL‐17 antibody, and the frequency of IL‐17‐secreting HICs decreased. NASH‐HICs enhanced proliferation of HSCs, in which proliferation was sensitive to IL‐17 stimulation. The stimulatory effect of NASH‐HICs on the activation of HSCs was attenuated by co‐culture with ADSCs.
Conclusion
ADSCs treatment prevented progression of NASH fibrosis by suppressing IL‐17‐mediated inflammation, which was associated with HSCs activation.