title: Adipose- and Bone Marrow-Derived Mesenchymal Stem Cells Prolong Graft Survival in Vascularized Composite Allotransplantation.
abstract: BACKGROUND
  Strategies aiming at minimization or elimination of systemic immunosuppression are key immediate goals for clinical expansion of vascularized composite allotransplantation (VCA). We compared the in vitro and in vivo immunomodulatory efficacy of adipose-derived mesenchymal stem cells (AD-MSCs) and bone marrow (BM)-derived MSCs in a rat VCA model.
  
  
  METHODS
  Both cell types were tested in vitro for suppressor function using mixed lymphocyte reactivity assays. AD-MSCs or BM-MSCs were administered intravenously (1 × 10 or 5 × 10 cells/animal) to Lewis rat recipients of mismatched Brown Norway hindlimb transplants. Short course tacrolimus (FK-506) monotherapy was withdrawn at postoperative day 21. In vivo regulatory T-cell induction, peripheral blood chimerism, and microchimerism in lymphatic organs were analyzed.
  
  
  RESULTS
  AD-MSCs and BM-MSCs exhibited strong dose-dependent suppressor function in vitro, which was significantly more pronounced for AD cells. In vivo, all animals revealed peripheral multi-lineage chimerism at four weeks (P < 0.01) independent of cell type and dosage. Regulatory T-cell levels were increased with both cell types, the most in AD-MSC groups. These immunomodulatory effects were only transient. MSC treatment resulted in long-term (>120 day) allograft survival in 47% of the animals, which correlated with durable microchimerism in BM and spleen.
  
  
  CONCLUSIONS
  AD-MSCs and BM-MSCs exert immunomodulatory effects that prolong survival of immunogenic skin-bearing VCA grafts with short course (21 day) tacrolimus induction therapy. The in vivo findings in terms of allograft survival did not reflect superior immunomodulatory characteristics of AD-MSCs found in vitro.
authors.affiliation: 1 Department of Plastic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA. 2 McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA. 3 Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Switzerland. 4 Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Gueishan, Taiwan. 5 Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Plock
authors.forename: Jonas T
authors.initials: JT
authors.lastname: Schnider
authors.forename: Wensheng
authors.initials: W
authors.lastname: Zhang
authors.forename: Riccardo
authors.initials: R
authors.lastname: Schweizer
authors.forename: Wakako
authors.initials: W
authors.lastname: Tsuji
authors.forename: Nataliya
authors.initials: N
authors.lastname: Kostereva
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Fanzio
authors.forename: Sudheer
authors.initials: S
authors.lastname: Ravuri
authors.forename: Mario G
authors.initials: MG
authors.lastname: Solari
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Cheng
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Rubin
authors.forename: Kacey G
authors.initials: KG
authors.lastname: Marra
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Gorantla
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D064595:Composite Tissue Allografts / Q000098:blood supply* / Q000187:drug effects / Q000637:transplantation*; D004334:Drug Administration Schedule; D006085:Graft Survival / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply* / Q000187:drug effects / Q000637:transplantation*; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016559:Tacrolimus / Q000008:administration & dosage; D013997:Time Factors; D018183:Transplantation Chimera; D023001:Transplantation Tolerance; D063986:Vascularized Composite Allotransplantation
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus