Adipose-Derived Stem Cells Ameliorate Experimental Murine Colitis via TSP-1-Dependent Activation of Latent TGF-β

Hiroshi Takeyama, Tsunekazu Mizushima, Mamoru Uemura, Naotsugu Haraguchi, Junichi Nishimura, Taishi Hata, Chu Matsuda, Ichiro Takemasa, Masakazu Ikenaga, Kohei Murata, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori

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Background: Adipose tissue-derived stem cells (ASCs) have been investigated as therapeutic tools for a variety of autoimmune diseases, including inflammatory diseases. However, the mechanisms underlying the immunomodulatory properties of ASCs are not well understood. Here, we investigated the mechanism of regulatory T cell (Treg) induction in ASC therapy in a murine model of inflammatory bowel disease. Methods: Acute colitis was induced in mice using dextran sulfate sodium and ASCs administered intraperitoneally. Tregs and CD103+ dendritic cells were analyzed in the mesenteric lymph nodes (MLNs), spleen, and colonic lamina propria (CLP). Activation of latent TGF-β by ASCs was analyzed in vitro using ELISA. siRNA technology was used to create ASCs in which TSP-1 or integrinαv was knocked down in order to investigate the involvement of these proteins in the activation of latent TGF-β. In addition, TSP-1-knockdown ASCs were administered to mice with colitis to assess their clinical efficacy in vivo. Results: Systemic administration of ASCs significantly lessened the clinical and histopathological severity of colitis. ASCs were distributed throughout the lymphatic system in the MLNs and spleen. Tregs were increased in the MLNs and CLP, but CD103+ dendritic cells were not significantly altered. The ASCs activated latent TGF-β. TSP-1 knockdown impaired TGF-β activation in vitro and abrogated the therapeutic effects of the ASCs in vivo. Furthermore, Tregs were not increased in the MLNs and CLP from mice treated with TSP-1-knockdown ASCs. Conclusions: These results demonstrate that ASCs induce Tregs by activating latent TGF-β via TSP-1, independent of CD103+ dendritic cell induction.

元の言語英語
ページ(範囲)1963-1974
ページ数12
ジャーナルDigestive Diseases and Sciences
62
発行部数8
DOI
出版物ステータス出版済み - 8 1 2017
外部発表Yes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Gastroenterology

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    Takeyama, H., Mizushima, T., Uemura, M., Haraguchi, N., Nishimura, J., Hata, T., Matsuda, C., Takemasa, I., Ikenaga, M., Murata, K., Yamamoto, H., Doki, Y., & Mori, M. (2017). Adipose-Derived Stem Cells Ameliorate Experimental Murine Colitis via TSP-1-Dependent Activation of Latent TGF-β. Digestive Diseases and Sciences, 62(8), 1963-1974. https://doi.org/10.1007/s10620-017-4578-y