title: Autologous mesenchymal stem cells prevent transplant arteriosclerosis by enhancing local expression of interleukin-10, interferon-γ, and indoleamine 2,3-dioxygenase.
abstract: Transplant arteriosclerosis (TA) remains the major limitation of long-term graft survival in heart transplantation despite the advances in immunosuppressants. Mesenchymal stem cells (MSCs) have been demonstrated to suppress allogeneic immune responses by numerous in vitro studies. However,  the immunomodulatory effects of MSCs in vivo are controversial and the underlying molecular mechanisms are not conclusive. In this study, we investigated the therapeutic potential of autologous bone marrow-derived MSCs on TA in a porcine model of femoral artery transplantation. MSCs or saline  were injected into the soft tissue surrounding the arterial grafts immediately postanastomosis. Four weeks after transplantation, neointimal formation increased significantly in untreated allografts compared with the MSC-treated grafts as assessed by intravascular ultrasound (maximum luminal  area stenosis: 40 ± 12% vs. 18 ± 6%, p < 0.001). Grafts harvested at 4 weeks showed dense perivascular lymphocyte infiltration accompanied by significant intimal hyperplasia in the untreated but not in the MSC-treated allografts. Serial angiographic examination showed  that all of the untreated allografts became occluded at the 8th week whereas the majority of the MSC-treated grafts remained patent at the 12th week posttransplantation (n = 12 each group, p < 0.001). Quantitative PCR analysis revealed that Foxp3 expression was comparable  between the untreated and the MSC-treated groups. However, expression of interleukin-10 (IL-10), interferon-γ (IFN-γ), and indoleamine 2,3-dioxygenase (IDO) was increased significantly in the MSC-treated allografts compared with that in the allograft controls (p = 0.021  for IL-10, p = 0.003 for IFN-γ, and p = 0.008 for IDO). In conclusion, local delivery of autologous MSCs alleviates TA by inducing allograft tolerance via enhanced expression of IL-10, IFN-γ, and IDO but not Foxp3-positive cells in the vessel wall. These results suggest  that MSCs induce immune tolerance by activating the type 1 regulatory T-like cells.
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Hsiang-Yiang
authors.initials: HY
authors.lastname: Jui
authors.forename: Cheng-Hsin
authors.initials: CH
authors.lastname: Lin
authors.forename: Wan-Tseng
authors.initials: WT
authors.lastname: Hsu
authors.forename: Yi-Ru
authors.initials: YR
authors.lastname: Liu
authors.forename: Ron-Bin
authors.initials: RB
authors.lastname: Hsu
authors.forename: Bor-Luen
authors.initials: BL
authors.lastname: Chiang
authors.forename: Wen-Yih I
authors.initials: WY
authors.lastname: Tseng
authors.forename: Ming-Fong
authors.initials: MF
authors.lastname: Chen
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
authors.forename: Chii-Ming
authors.initials: CM
authors.lastname: Lee
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000517:prevention & control*; D001854:Bone Marrow Cells / Q000166:cytology; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000000981:diagnostic imaging / Q000378:metabolism / Q000637:transplantation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006085:Graft Survival; D007165:Immunosuppression Therapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D013552:Swine; D014162:Transfection; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous; D014463:Ultrasonography
chemical_list: D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016753:Interleukin-10; D007371:Interferon-gamma