title: Mesenchymal stem cells as a gene delivery vehicle for successful islet transplantation.
abstract: OBJECTIVE
  To evaluate the efficacy of human bone marrow-derived mesenchymal stem cells (hBMSCs) as gene delivery vehicles to simultaneously express human hepatocyte growth factor (HGF) and interleukin 1 receptor antagonist (IL-1Ra) to improve the outcome of islet transplantation.
  
  
  METHODS
  Morphology and islet-binding affinity of hBMSCs were checked by microscope. The expression of target genes and endogenous genes was determined by ELISA. Protection of islets by hBMSCs was evaluated in vitro by Calcein-AM/Propidium Iodide staining and in vivo by allogeneic islet transplantation study. Function and revascularization of islets was evaluated by immune fluorescence study.
  
  
  RESULTS
  Non-donor-specific hBMSCs showed strong binding affinity to human islets and protected viability and function. Transduction of hBMSCs with adenovirus encoding human HGF and human IL-1Ra (Adv-hHGF-hIL-1Ra) prior to co-culturing with islets further protected from apoptotic cell death, helped maintain 3D structures and morphology, and enhanced insulin secretion. Transplantation of human islets reconstituted with Adv-hHGF-hIL-1Ra transduced hBMSCs under the kidney capsule of streptozotocin-induced diabetic non-obese diabetic/severe combined immunodeficient (NOD-SCID) mice reversed diabetes by reducing blood glucose levels to ≤ 200 mg/dL for up to 15 weeks and reduced the number of islets required to achieving normoglycemia. Blood glucose levels of mice transplanted with islets alone reversed to ≥ 500 mg/dL 4 weeks post-transplantation.
  
  
  CONCLUSIONS
  Results indentified hBMSCs as effective gene delivery vehicles to improve the outcome of islet transplantation.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 19 S. Manassas, RM 224, Memphis, Tennessee 38103-3308, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Wenli
authors.initials: W
authors.lastname: Lu
authors.forename: Ram I
authors.initials: RI
authors.lastname: Mahato
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000601:surgery; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D005951:Glucose Tolerance Test; D006084:Graft Rejection / Q000235:genetics / Q000517:prevention & control; D006085:Graft Survival / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics*; D007515:Islets of Langerhans / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D018919:Neovascularization, Physiologic
chemical_list: D001786:Blood Glucose; C507763:IL1RN protein, human; D007328:Insulin; D053590:Interleukin 1 Receptor Antagonist Protein; D017228:Hepatocyte Growth Factor