Ex vivo Pretreatment of Islets with Mitomycin C

Cell Transplantation

Original Articles

Ikuo Wada¹  Naoya Sato²  Mitsukazu Gotoh²  Takashi Kimura²  Shigeru Marubashi²  Junichiro Haga²  Akira Kenjo²  Tsutomu Mori³  Takayuki Anazawa⁴ 

[1] Department of Cell Science, Institute of Biomedical Sciences, Fukushima Medical University, Hikarigaoka, Fukushima, Japan;Department of Hepato-Biliary-Pancreatic and Transplant Surgery, Fukushima Medical University, Hikarigaoka, Fukushima, Japan;Department of Human Lifesciences, School of Nursing, Fukushima Medical University, Hikarigaoka, Fukushima, Japan;Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan;

关键词: islets transplantation;    preconditioning;    inflammation;    tolerance;   

DOI  :  10.1177/0963689717721233

 received in 2017-03-05, accepted in 2017-04-21,  发布年份 2017

来源: Sage Journals

【 摘 要 】

Strategies to reduce the immunogenicity of pancreatic islets and to prevent the activation of proinflammatory events are essential for successful islet engraftment. Pretransplant islet culture presents an opportunity for preconditioning to improve outcomes of islet transplantation. We previously demonstrated that ex vivo mitomycin C (MMC) pretreatment and subsequent culture significantly prolonged graft survival. Fully understanding the biological process of pretreatment could result in the development of a protocol to improve the survival of islet grafts. Microarrays were employed to conduct a comprehensive analysis of genes expressed in untreated or MMC-treated rat islets that were subsequently cultured for 3 d. A bioinformatics software was used to identify biological processes that were most affected by MMC pretreatment, and validation studies, including in vivo and in vitro assay, were performed. The gene expression analysis identified significant downregulation of annotated functions associated with cellular movement and revealed significant downregulation of multiple genes encoding proinflammatory mediators with chemotactic activity. Validation studies revealed significantly decreased levels of interleukin 6 (IL-6), monocyte chemoattractant protein 3 (MCP-3), and matrix metallopeptidase 2 (MMP2) in culture supernatants of MMC-treated islets compared with controls. Moreover, we showed the suppression of leukocyte chemotactic activity of MMC-treated islets in vitro. We also showed that MMC-treated islets secreted lower levels of chemoattractants that synergistically reduced the immunogenic potential of islets. Histological and immunohistochemical analyses of the implant site revealed that infiltration of monocytes, CD3-positive T cells, and B cells was decreased in MMC-treated islets. In conclusion, the ex vivo pretreatment of islets with MMC and subsequent culture can reduce the immunogenic potential and prolong the survival of islet grafts by inducing the suppression of multiple leukocyte chemotactic factors.

【 授权许可】

CC BY-NC   
© The Author(s) 2017

【 图 表 】

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