title: Adipose tissue-derived stem cells suppress acute cellular rejection by TSG-6 and CD44 interaction in rat kidney transplantation.
abstract: 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 (2×10) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Taigo
authors.initials: T
authors.lastname: Kato
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Okumi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tanemura
authors.forename: Koji
authors.initials: K
authors.lastname: Yazawa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kakuta
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yamanaka
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsutahara
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Shiro
authors.initials: S
authors.lastname: Takahara
authors.forename: Norio
authors.initials: N
authors.lastname: Nonomura
mesh_terms: D000208:Acute Disease; D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000502:physiology*; D016207:Cytokines / Q000032:analysis; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D018960:Hyaluronan Receptors / Q000502:physiology*; D016030:Kidney Transplantation; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D018960:Hyaluronan Receptors; C513056:Tnfaip6 protein, rat