title: iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation.
abstract: Mesenchymal stem cell (MSC) differentiation is dramatically reduced after long-term in vitro culture, which limits their application. MSCs derived from induced pluripotent stem cells (iPSCs-MSCs) represent a novel source of MSCs. In this study, we investigated the therapeutic effect of iPSC-MSCs on diabetic mice. Streptozocin-induced diabetic mice transplanted with 400 islets alone or with 1×10(6) iPSC-MSCs were examined following rapamycin injection (0.1 mg/kg/day, i.p., from days 0 to 9) after transplantation. Our results showed that iPSC-MSCs combined with rapamycin significantly prolonged islet allograft survival in the diabetic mice; 50% of recipients exhibited long-term survival (>100 days). Histopathological analysis revealed that iPSC-MSCs combined with rapamycin preserved the graft effectively, inhibited inflammatory cell infiltration, and resulted in substantial release of insulin. Flow cytometry results showed that the proportion of CD4(+) and CD8(+) T cells was significantly reduced, and the number of T regulatory cells increased in the spleen and lymph nodes in the iPSC-MSCs combined with the rapamycin group compared with the rapamycin-alone group. Production of the Th1 proinflammatory cytokines interleukin-2 (IL-2) and interferon-γ was reduced, and secretion of the anti-inflammatory cytokines IL-10 and transforming growth factor-β was enhanced compared with the rapamycin group, as determined using enzyme-linked immunosorbent assays. Transwell separation significantly weakened the immunosuppressive effects of iPSC-MSCs on the proliferation of Con A-treated splenic T cells, which indicated that the combined treatment exerted immunosuppressive effects through cell-cell contact and regulation of cytokine production. Taken together, these findings highlight the potential application of iPSC-MSCs in islet transplantation.
authors: 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China .|2 Qingdao Municipal Centers for Disease Control and Prevention , Qingdao City, Shandong Province, People's Republic of China .
authors: Pan-Pan
authors: PP
authors: Cheng
authors: 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China .
authors: Xiao-Cun
authors: XC
authors: Liu
authors: 3 State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai City, People's Republic of China .
authors: Peng-Fei
authors: PF
authors: Ma
authors: 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China .
authors: Chang
authors: C
authors: Gao
authors: 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China .
authors: Jia-Li
authors: JL
authors: Li
authors: 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China .
authors: Ying-Ying
authors: YY
authors: Lin
authors: 4 The Affiliated Chenggong Hospital of Xiamen University , Xiamen City, Fujian Province, People's Republic of China .
authors: Wei
authors: W
authors: Shao
authors: 4 The Affiliated Chenggong Hospital of Xiamen University , Xiamen City, Fujian Province, People's Republic of China .
authors: Shuo
authors: S
authors: Han
authors: 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China .
authors: Bin
authors: B
authors: Zhao
authors: 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China .
authors: Lu-Min
authors: LM
authors: Wang
authors: 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China .
authors: Jia-Zhao
authors: JZ
authors: Fu
authors: 5 The First Affiliated Hospital of Xiamen University , Xiamen City, Fujian Province, People's of Republic of China .
authors: Lu-Xi
authors: LX
authors: Meng
authors: 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China .
authors: Qing
authors: Q
authors: Li
authors: 6 Departments of Ophthalmology and Medicine, University of Hong Kong , Pokfulam, Hong Kong, People's Republic of China .
authors: Qi-Zhou
authors: QZ
authors: Lian
authors: 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China .
authors: Jun-Jie
authors: JJ
authors: Xia
authors: 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China .
authors: Zhong-Quan
authors: ZQ
authors: Qi
mesh_terms: D064591:Allografts; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D057026:Induced Pluripotent Stem Cells / Q000276:immunology / Q000637:transplantation; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D020123:Sirolimus / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D023001:Transplantation Tolerance
chemical_list: D020123:Sirolimus