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Adipose Tissue-Derived Stem Cells Suppress Acute Cellular Rejection by TSG-6 and CD44 Interaction in Rat Kidney Transplantation

Kato, Taigo1; Okumi, Masayoshi1,5; Tanemura, Masahiro2,5; Yazawa, Koji1; Kakuta, Yoichi1; Yamanaka, Kazuaki1; Tsutahara, Koichi1; Doki, Yuichiro3; Mori, Masaki3; Takahara, Shiro4; Nonomura, Norio1

doi: 10.1097/TP.0000000000000230
Basic and Experimental Research

Background: In addition to its abundance and easy accessibility, adipose tissue yields more potent immunoregulatory stem cells (adipose tissue-derived stem cells, ADSCs) than does bone marrow. However, the beneficial effects of ADSCs on alloreactivity are scarcely known. This study evaluated the beneficial effects of ADSCs in rat kidney transplantation and analyzed the underlying molecular mechanism.

Methods: Dark Agouti rat kidneys were transplanted into Lewis rats. Autologous ADSCs (2×106) were injected through the left renal artery of the donors before the nephrectomy (ADSCs group). Graft survival, histologic changes, and the expression of several cytokines and proteins were assessed. In an in vitro experiment, the immunosuppressive capacity of ADSCs was tested in a mixed lymphocyte reaction.

Results: Histologic findings of the ADSCs group revealed a reduced rejection grade, whereas the number of infiltrated CD4+/CD8+ T cells was also significantly decreased as compared to the control. Relative to these findings, injection of ADSCs led to a significantly prolonged mean graft survival compared with the control. In vitro, autologous ADSCs dose-dependently suppressed alloreactive lymphocytes. Moreover, ADSCs increased the level of tumor necrosis factor-inducible gene 6 protein (TSG-6) in mixed lymphocyte reaction, which has an anti-inflammatory capacity. Recombinant TSG-6 markedly suppressed alloreactive T cells through downregulating CD44, which may lead to the suppression of T-cell activation and infiltration into allografts.

Conclusion: Our findings clearly showed that ADSCs attenuated acute rejection by secreting TSG-6 as well as through direct cell interaction. These findings contribute to the clinical application of these cells in solid organ transplantation.

1 Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.

2 Department of Gastroenterological Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan.

3 Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

4 Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan.

5 Address correspondence to: Masayoshi Okumi, M.D., Ph.D., Department of Urology, Osaka University Graduate School of Medicine, 2-2 E4 Yamadaoka, Suita, Osaka 565-0871, Japan; Masahiro Tanemura, M.D., Ph.D., Department of Gastroenterological Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, 3-1 Aoyamacho, Kure, Hiroshima 737-0023, Japan.

This work was supported by a Grant-in-Aid for Scientific Research (C) (25462536 to M.O.) and a Grant-in-Aid for Young Scientists (B) (25861419 to T.K.) from the Japan Society for the Promotion of Science.

The authors declare no conflicts of interest.

E-mail: okumi@uro.med.osaka-u.ac.jp; tanemuram@kure-nh.go.jp

T.K. designed the study, conducted the experiments, performed data analysis, and drafted the article. M.O. and M.T provided the study design and the working hypothesis and completed the article. K.Y. provided the study design and the working hypothesis. Y.K., K.Y, and K.T provided scientific advice. Y.D., M.M., S.T., and N.N. provided guidance throughout the study.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Received 11 October 2013. Revision requested 11 November 2013.

Accepted 8 April 2014.

© 2014 by Lippincott Williams & Wilkins