title: Impact of ex vivo administration of mesenchymal stem cells on the function of kidney grafts from cardiac death donors in rat.
abstract: BACKGROUND
  Mesenchymal stem cells (MSCs) have been applied to the treatment of various diseases, and MSC administration in marginal donor grafts may help avoid the ischemia-reperfusion injury associated with solid organ transplants. Given the reports of side effects after intravenous MSC administration, local MSC administration to the target organ might be a better approach. We administered adipose tissue-derived MSCs (AT-MSCs) ex vivo to donor rat kidneys obtained after cardiac death (CD).
  
  
  METHODS
  Using male Lewis rats (8-10 weeks), and a marginal transplant model of 1hr CD plus 1hr sub-normothermic ET-Kyoto solution preservation were conducted. AT-MSCs obtained from double-reporter (luciferase-LacZ) transgenic Lewis rats were injected either systemically (1.0 × 10(6) cells/0.5 mL) to bilaterally nephrectomized recipient rats that had received a marginal kidney graft (n = 6), or locally via the renal artery (500 μL ET-Kyoto solution containing the same number of AT-MSCs) to marginal kidney grafts, which were then preserved (1 hour; 22°C) before being transplanted into bilaterally nephrectomized recipient rats (n = 8). Serum was collected to assess the therapeutic effects of AT-MSC administration, and the recipients of rats surviving to Day 14 were separately evaluated histopathologically. Follow-up was by in vivo imaging and histological LacZ staining, and tumor formation was evaluated in MSC-injected rats at 3 months.
  
  
  RESULTS
  Systemic injection of MSC did not improve recipient survival. In vivo imaging showed MSCs trapped in the lung that later became undetectable. Ex vivo injection of MSCs did show a benefit without adverse effects. At Day 14 after RTx, 75% of the rats in the AT-MSC-injected group (MSC[+]) had survived, whereas 50% of the rats in the AT-MSC-non-injected group (MSC[-]) had died. Renal function in the MSC(+) group was improved compared with that in the MSC(-) group at Day 4. LacZ staining revealed AT-MSCs attached to the renal tubules at 24 hours after RTx that later became undetectable. Histopathologic examination showed little difference in fibrosis between the groups at Day 14. No teratomas or other abnormalities were seen at 3 months.
authors.affiliation: Laboratory of Small Animal Surgery I, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan. Electronic address: iwai@vmas.kitasato-u.ac.jp.
authors.forename: S
authors.initials: S
authors.lastname: Iwai
authors.affiliation: Laboratory of Small Animal Surgery I, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Sakonju
authors.affiliation: Laboratory of Small Animal Surgery II, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Okano
authors.affiliation: Division of Development of Advanced Therapy, Center for Development of Advanced Medical Technology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Teratani
authors.affiliation: Division of Development of Advanced Therapy, Center for Development of Advanced Medical Technology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kasahara
authors.affiliation: Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yokote
authors.affiliation: Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yokoo
authors.affiliation: Division of Development of Advanced Therapy, Center for Development of Advanced Medical Technology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Kobayash
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D003643:Death; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D051381:Rats; D011917:Rats, Inbred Lew; D014019:Tissue Donors