title: Intravenous vs intraperitoneal mesenchymal stem cells administration: what is the best route for treating experimental colitis?
abstract: OBJECTIVE
  To investigate the therapeutic effects of mesenchymal stem cells (MSCs) transplanted intraperitoneally and intravenously in a murine model of colitis.
  
  
  METHODS
  MSCs were isolated from C57BL/6 mouse adipose tissue. MSC cultures were analyzed according to morphology, cellular differentiation potential, and surface molecular markers. Experimental acute colitis was induced in C57BL/6 mice by oral administration of 2% dextran sulfate sodium (DSS) in drinking water ad libitum from days 0 to 7. Colitis mice were treated with 1 × 10(6) MSCs via intraperitoneal or intravenous injection on days 2 and 5. The disease activity index was determined daily based on the following parameters: weight loss, stool consistency and presence of blood in the feces and anus. To compare morphological and functional differences in tissue regeneration between different MSC injection modalities, mice were euthanized on day 8, and their colons were examined for length, weight, and histopathological changes. Inflammatory responses were determined by measuring the levels of different serum cytokines using a CBA Th1/Th2/Th17 kit. Apoptotic rates were evaluated by terminal deoxynucleotidyl transferase-mediated dUDP-biotin nick end labeling assay.
  
  
  RESULTS
  Intravenous infusion of MSCs was more effective than intraperitoneal treatment (P < 0.001) in reducing the clinical and histopathologic severity of colitis, which includes weight loss, diarrhea and inflammation. An histological evaluation demonstrated decreased colonic inflammation based on reduced crypt loss and reduced infiltration of inflammatory cells. This therapeutic effect was most likely mediated by the down-regulation of pro-inflammatory cytokines [interleukin (IL)-6 and tumor necrosis factor (TNF)]; and by the up-regulation of anti-inflammatory cytokines (IL-10 and IL-4). Intravenous transplantation also induced high levels of IFN that lead to activation of the immunosuppressive activity of the MSCs, which did not occur with intraperitoneal transplantation (P = 0.006). An increase in apoptotic T cells was observed after intravenous, but not intraperitoneal, MSC infusion, suggesting that MSCs can induce apoptosis in resistant T cells in colonic inflammation (P = 0.027).
  
  
  CONCLUSIONS
  Our results demonstrate that intravenous treatment is a superior method for reducing colon inflammation compared with intraperitoneal therapy.
authors.affiliation: Fabiany da Costa Gonçalves, Natália Schneider, Fernanda Otesbelgue Pinto, Fabíola Schons Meyer, Bianca Pfaffenseller, Eduardo Pandolfi Passos, Elizabeth Obino Cirne-Lima, Ana Helena Paz, Centro de Pesquisa Experimental do Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil.
authors.forename: Fabiany da Costa
authors.initials: Fda C
authors.lastname: Gonçalves
authors.affiliation: Fabiany da Costa Gonçalves, Natália Schneider, Fernanda Otesbelgue Pinto, Fabíola Schons Meyer, Bianca Pfaffenseller, Eduardo Pandolfi Passos, Elizabeth Obino Cirne-Lima, Ana Helena Paz, Centro de Pesquisa Experimental do Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil.
authors.forename: Natália
authors.initials: N
authors.lastname: Schneider
authors.affiliation: Fabiany da Costa Gonçalves, Natália Schneider, Fernanda Otesbelgue Pinto, Fabíola Schons Meyer, Bianca Pfaffenseller, Eduardo Pandolfi Passos, Elizabeth Obino Cirne-Lima, Ana Helena Paz, Centro de Pesquisa Experimental do Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil.
authors.forename: Fernanda Otesbelgue
authors.initials: FO
authors.lastname: Pinto
authors.affiliation: Fabiany da Costa Gonçalves, Natália Schneider, Fernanda Otesbelgue Pinto, Fabíola Schons Meyer, Bianca Pfaffenseller, Eduardo Pandolfi Passos, Elizabeth Obino Cirne-Lima, Ana Helena Paz, Centro de Pesquisa Experimental do Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil.
authors.forename: Fabíola Schons
authors.initials: FS
authors.lastname: Meyer
authors.affiliation: Fabiany da Costa Gonçalves, Natália Schneider, Fernanda Otesbelgue Pinto, Fabíola Schons Meyer, Bianca Pfaffenseller, Eduardo Pandolfi Passos, Elizabeth Obino Cirne-Lima, Ana Helena Paz, Centro de Pesquisa Experimental do Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Visioli
authors.affiliation: Fabiany da Costa Gonçalves, Natália Schneider, Fernanda Otesbelgue Pinto, Fabíola Schons Meyer, Bianca Pfaffenseller, Eduardo Pandolfi Passos, Elizabeth Obino Cirne-Lima, Ana Helena Paz, Centro de Pesquisa Experimental do Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil.
authors.forename: Bianca
authors.initials: B
authors.lastname: Pfaffenseller
authors.affiliation: Fabiany da Costa Gonçalves, Natália Schneider, Fernanda Otesbelgue Pinto, Fabíola Schons Meyer, Bianca Pfaffenseller, Eduardo Pandolfi Passos, Elizabeth Obino Cirne-Lima, Ana Helena Paz, Centro de Pesquisa Experimental do Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil.
authors.forename: Patrícia Luciana da Costa
authors.initials: PL
authors.lastname: Lopez
authors.affiliation: Fabiany da Costa Gonçalves, Natália Schneider, Fernanda Otesbelgue Pinto, Fabíola Schons Meyer, Bianca Pfaffenseller, Eduardo Pandolfi Passos, Elizabeth Obino Cirne-Lima, Ana Helena Paz, Centro de Pesquisa Experimental do Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil.
authors.forename: Eduardo Pandolfi
authors.initials: EP
authors.lastname: Passos
authors.affiliation: Fabiany da Costa Gonçalves, Natália Schneider, Fernanda Otesbelgue Pinto, Fabíola Schons Meyer, Bianca Pfaffenseller, Eduardo Pandolfi Passos, Elizabeth Obino Cirne-Lima, Ana Helena Paz, Centro de Pesquisa Experimental do Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil.
authors.forename: Elizabeth Obino
authors.initials: EO
authors.lastname: Cirne-Lima
authors.affiliation: Fabiany da Costa Gonçalves, Natália Schneider, Fernanda Otesbelgue Pinto, Fabíola Schons Meyer, Bianca Pfaffenseller, Eduardo Pandolfi Passos, Elizabeth Obino Cirne-Lima, Ana Helena Paz, Centro de Pesquisa Experimental do Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil.
authors.forename: Luíse
authors.initials: L
authors.lastname: Meurer
authors.affiliation: Fabiany da Costa Gonçalves, Natália Schneider, Fernanda Otesbelgue Pinto, Fabíola Schons Meyer, Bianca Pfaffenseller, Eduardo Pandolfi Passos, Elizabeth Obino Cirne-Lima, Ana Helena Paz, Centro de Pesquisa Experimental do Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil.
authors.forename: Ana Helena
authors.initials: AH
authors.lastname: Paz
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D003092:Colitis / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D003106:Colon / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016207:Cytokines / Q000097:blood; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000097:blood; D007262:Infusions, Intravenous; D007263:Infusions, Parenteral; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010641:Phenotype; D012038:Regeneration; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D016264:Dextran Sulfate
keywords: Cell transplantation; Dextran sulfate sodium; Immunomodulation; Inflammatory bowel disease; Intravenous injection; Mesenchymal stem cell; Ulcerative colitis