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

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1963-1974
Number of pages12
JournalDigestive Diseases and Sciences
Volume62
Issue number8
DOIs
Publication statusPublished - Aug 1 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Gastroenterology

Fingerprint Dive into the research topics of 'Adipose-Derived Stem Cells Ameliorate Experimental Murine Colitis via TSP-1-Dependent Activation of Latent TGF-β'. Together they form a unique fingerprint.

  • Cite this

    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