Original Article
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 28, 2014; 20(48): 18228-18239
Published online Dec 28, 2014. doi: 10.3748/wjg.v20.i48.18228
Intravenous vs intraperitoneal mesenchymal stem cells administration: What is the best route for treating experimental colitis?
Fabiany da Costa Gonçalves, Natália Schneider, Fernanda Otesbelgue Pinto, Fabíola Schons Meyer, Fernanda Visioli, Bianca Pfaffenseller, Patrícia Luciana da Costa Lopez, Eduardo Pandolfi Passos, Elizabeth Obino Cirne-Lima, Luíse Meurer, Ana Helena Paz
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
Fabiany da Costa Gonçalves, Natália Schneider, Patrícia Luciana da Costa Lopez, Luíse Meurer, Ana Helena Paz, Programa de Pós-Graduação: Ciências em Gastroenterologia e Hepatologia, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
Fernanda Visioli, Faculdade de Odontologia, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
Author contributions: Gonçalves FC and Paz AH designed the study; Gonçalves FC, Schneider N, Pinto FO, Meyer FS, Pfaffenseller B and Paz AH performed the research; Gonçalves FC, Visioli F and Paz AH participated in the interpretation of the data; Gonçalves FC, Lopez PLC and Paz AH wrote the paper; Passos EP, Cirne-lima EO, Meurer L and Paz AH supervised the study design, execution, analysis, and approved the final version.
Supported by Fundo de Incentivo à Pesquisa e Eventos do Hospital de Clínicas de Porto Alegre and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Correspondence to: Ana Helena Paz, PhD, Professor of Programa de Pós-Graduação: Ciências em Gastroenterologia e Hepatologia, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos 2350, Porto Alegre 90035-903, Rio Grande do Sul, Brazil. anahpaz@gmail.com
Telephone: +55-51-33598840 Fax: +55-51-33598761
Received: April 17, 2014
Revised: June 28, 2014
Accepted: August 13, 2014
Published online: December 28, 2014
Processing time: 264 Days and 4.9 Hours
Abstract

AIM: 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 × 106 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).

CONCLUSION: Our results demonstrate that intravenous treatment is a superior method for reducing colon inflammation compared with intraperitoneal therapy.

Keywords: Ulcerative colitis; Dextran sulfate sodium; Inflammatory bowel disease; Mesenchymal stem cell; Cell transplantation; Intravenous injection; Immunomodulation

Core tip: After receiving appropriate biological signals during injury or tissue inflammation, mesenchymal stem cells (MSCs) can migrate to the affected site and suppress effector T cells to modulate inflammatory responses and tissue regeneration. Currently, little is known regarding the optimal delivery strategy for MSCs for the treatment of ulcerative colitis. To our knowledge, no studies have shown which method of cell transplantation is best for the treatment of colon inflammation. The present study demonstrates that intravenous treatment resulted in reduced colon inflammation and is the best route for cell therapy in ulcerative colitis.