title: Therapeutic efficacy and biodistribution of allogeneic mesenchymal stem cells delivered by intrasplenic and intrapancreatic routes in streptozotocin-induced diabetic mice.
abstract: BACKGROUND
  Mesenchymal stromal/stem cells (MSCs) are multipotent cells that have the ability to express and secrete a wide range of immunomodulatory molecules, cytokines, growth factors and antiapoptotic proteins. MSCs modulate both innate and adaptive immune responses making them potential candidates for the treatment of patients with type 1 diabetes mellitus (T1D). However, one problem frequently associated with the systemic MSCs administration is the entrapment of the cells mainly in the lungs. In this sense, trying to avoid the lung barrier, the purpose of this study was to evaluate the long-term therapeutic efficacy and biodistribution of allogeneic adipose tissue-derived MSCs (ADMSCs) injected via two different delivery routes (intrasplenic/I.Sp and intrapancreatic/I.Pc) in a murine model of diabetes induced by streptozotocin (STZ).
  
  
  METHODS
  Experimental diabetes was induced in C57BL/6 male mice by multiple low-doses of STZ. MSCs were isolated from adipose tissue (ADMSCs) of Balb/c mice. A single dose of 1x10(6) ADMSCs was microinjected into the spleen or into the pancreas of diabetic mice. Control group received injection of PBS by I.Sp or I.Pc delivery routes. Glycemia, peripheral glucose response, insulin-producing β cell mass, regulatory T cell population, cytokine profile and cell biodistribution were evaluated after ADMSCs/PBS administration.
  
  
  RESULTS
  ADMSCs injected by both delivery routes were able to decrease blood glucose levels and improve glucose tolerance in diabetic mice. ADMSCs injected by I.Sp route reverted hyperglycemia in 70% of diabetic treated mice, stimulating insulin production by pancreatic β cells. Using the I.Pc delivery route, 42% of ADMSCs-treated mice responded to the therapy. Regulatory T cell population remained unchanged after ADMSCs administration but pancreatic TGF-β levels were increased in ADMSCs/I.Sp-treated mice. ADMSCs administrated by I.Sp route were retained in the spleen and in the liver and ADMSCs injected by I.Pc route remained in the pancreas. However, ADMSCs injected by these delivery routes remained only few days in the recipients.
  
  
  CONCLUSIONS
  Considering the potential role of MSCs in the treatment of several disorders, this study reports alternative delivery routes that circumvent cell entrapment into the lungs promoting beneficial therapeutic responses in ADMSCs-treated diabetic mice.
authors.affiliation: Department of Biochemistry and Immunology, Basic and Applied Immunology Program, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil. ueda.juliana@gmail.com.|Tenente Catão Roxo 2501, Monte Alegre 14051-140, Ribeirão Preto, São Paulo, Brazil. ueda.juliana@gmail.com.
authors.forename: Juliana Navarro Ueda
authors.initials: JN
authors.lastname: Yaochite
authors.affiliation: Department of Biochemistry and Immunology, Basic and Applied Immunology Program, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil. carolina@hemocentro.fmrp.usp.br.
authors.forename: Carolina
authors.initials: C
authors.lastname: Caliari-Oliveira
authors.affiliation: Department of Clinical Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil. lucas.edubs@gmail.com.
authors.forename: Lucas Eduardo Botelho
authors.initials: LE
authors.lastname: de Souza
authors.affiliation: Department of Surgery and Anatomy, Pediatric Surgery Division, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil. sbragia@fmrp.usp.br.
authors.forename: Lourenço Sbragia
authors.initials: LS
authors.lastname: Neto
authors.affiliation: Regional Blood Center of Ribeirão Preto, University of São Paulo, Tenente Catão Roxo 2501, Monte Alegre 14051-140, Ribeirão Preto, São Paulo, Brazil. palmapvb@zipmail.com.br.
authors.forename: Patrícia Vianna Bonini
authors.initials: PV
authors.lastname: Palma
authors.affiliation: Department of Clinical Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil. dimascovas@gmail.com.
authors.forename: Dimas Tadeu
authors.initials: DT
authors.lastname: Covas
authors.affiliation: Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, Monte Alegre 14040-903, Ribeirão Preto, São Paulo, Brazil. kelenfarias@fcfrp.usp.br.
authors.forename: Kelen Cristina Ribeiro
authors.initials: KC
authors.lastname: Malmegrim
authors.forename: Julio César
authors.initials: JC
authors.lastname: Voltarelli
authors.affiliation: Department of Biochemistry and Immunology, Basic and Applied Immunology Program, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil. eadonadi@fmrp.usp.br.
authors.forename: Eduardo Antônio
authors.initials: EA
authors.lastname: Donadi
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D002465:Cell Movement; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D006943:Hyperglycemia / Q000628:therapy*; D007328:Insulin / Q000096:biosynthesis*; D050417:Insulin-Secreting Cells / Q000166:cytology; D008168:Lung / Q000166:cytology; D018655:Lymphocyte Count; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013154:Spleen / Q000166:cytology; D013311:Streptozocin; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D016212:Transforming Growth Factor beta; D013311:Streptozocin