title: Mesenchymal stem cell and islet co-transplantation promotes graft revascularization and function.
abstract: BACKGROUND
  Bone marrow-derived mesenchymal stem cells (MSCs) are known to produce vascular endothelial growth factor. We hypothesize that co-transplantation of MSCs and islets promotes revascularization and improves islet graft function.
  
  
  METHODS
  Lewis rat islets were infused into the liver of streptozotocin-diabetic syngeneic recipients or transplanted under the renal capsule of nonobese diabetic severe combined immunodeficiency (NOD SCID) mice with MSCs isolated from Lewis bone marrow and expanded in culture.
  
  
  RESULTS
  Co-transplantation of 500 islets and 107 MSCs (islet-MSCs) reversed diabetes in all eight recipients, whereas islet-alone transplantation achieved euglycemia in 3 of 10 recipients. With 300 islets, five of nine islet-MSCs and 1 of 10 islets-alone recipients reversed diabetes. Results of intravenous glucose tolerance tests performed on day 56 were significantly better in islet-MSCs than islet-alone recipients. One week after transplantation, well-preserved islet structure and higher number of capillaries were found in the liver of islet-MSCs recipients, whereas islet-alone grafts were fragmented with very few capillaries. Islets showed a similar morphology when transplanted with MSCs in nonobese diabetic severe combined immunodeficiency mice with a significantly higher capillary per [beta]-cell ratio than that in islet-alone grafts (0.135+/-0.046 vs. 0.052+/-0.028 capillary segments per [beta]-cell, P<0.01). One week after transplantation, islets were surrounded by MSCs labeled with carboxyfluorescein succinimidyl ester or Qdot nanocrystals, and some labeled MSCs positively stained for vascular endothelial growth factor or von Willebrand factor.
  
  
  CONCLUSIONS
  Our results demonstrate the improvement of islet graft morphology and function by co-transplantation with MSCs. This improvement is attributable, at least in part, to the promotion of graft revascularization mediated by MSCs.
authors.affiliation: Southern California Islet Cell Resources Center, Department of Diabetes, Endocrinology, and Metabolism, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Taihei
authors.initials: T
authors.lastname: Ito
authors.forename: Shin
authors.initials: S
authors.lastname: Itakura
authors.forename: Ivan
authors.initials: I
authors.lastname: Todorov
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rawson
authors.forename: Sadaki
authors.initials: S
authors.lastname: Asari
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shintaku
authors.forename: Indu
authors.initials: I
authors.lastname: Nair
authors.forename: Kevin
authors.initials: K
authors.lastname: Ferreri
authors.forename: Fouad
authors.initials: F
authors.lastname: Kandeel
authors.forename: Yoko
authors.initials: Y
authors.lastname: Mullen
mesh_terms: D000818:Animals; D002469:Cell Separation; D005434:Flow Cytometry; D005951:Glucose Tolerance Test; D006085:Graft Survival; D007150:Immunohistochemistry / Q000379:methods; D007515:Islets of Langerhans / Q000166:cytology*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D016513:Mice, SCID; D018919:Neovascularization, Physiologic; D051381:Rats; D011917:Rats, Inbred Lew; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D014841:von Willebrand Factor