title: Toll-like receptor 3 pre-conditioning increases the therapeutic efficacy of umbilical cord mesenchymal stromal cells in a dextran sulfate sodium-induced colitis model.
abstract: OBJECTIVE
  Immunomodulatory properties of human umbilical cord-derived mesenchymal stromal cells (UCMSCs) can be differentially modulated by toll-like receptors (TLR) agonists. Here, the therapeutic efficacy of short TLR3 and TLR4 pre-conditioning of UCMSCs was evaluated in a dextran sulfate sodium (DSS)-induced colitis in mice. The novelty of this study is that although modulation of human MSCs activity by TLRs is not a new concept, this is the first time that short TLR pre-conditioning has been carried out in a murine inflammatory model of acute colitis.
  
  
  METHODS
  C57BL/6 mice were exposed to 2.5% dextran sulfate sodium (DSS) in drinking water ad libitum for 7 days. At days 1 and 3, mice were injected intraperitoneally with 1 × 10(6) UCMSCs untreated or TLR3 and TLR4 pre-conditioned UCMSCs. UCMSCs were pre-conditioned with poly(I:C) for TLR3 and LPS for TLR4 for 1 h at 37°C and 5% CO2. We evaluated clinical signs of disease and body weights daily. At the end of the experiment, colon length and histological changes were assessed.
  
  
  RESULTS
  poly(I:C) pre-conditioned UCMSCs significantly ameliorated the clinical and histopathological severity of DSS-induced colitis compared with UCMSCs or LPS pre-conditioned UCMSCs. In contrast, infusion of LPS pre-conditioned UCMSCs significantly increased clinical signs of disease, colon shortening and histological disease index in DSS-induced colitis.
  
  
  CONCLUSIONS
  These results show that short in vitro TLR3 pre-conditioning with poly(I:C) enhances the therapeutic efficacy of UCMSCs, which is a major breakthrough for developing improved treatments to patients with inflammatory bowel disease.
authors.affiliation: Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fuenzalida
authors.affiliation: Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile.
authors.forename: Mónica
authors.initials: M
authors.lastname: Kurte
authors.affiliation: Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile.
authors.forename: Catalina
authors.initials: C
authors.lastname: Fernández-O'ryan
authors.affiliation: Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ibañez
authors.affiliation: Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile.
authors.forename: Melanie
authors.initials: M
authors.lastname: Gauthier-Abeliuk
authors.affiliation: Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Vega-Letter
authors.affiliation: Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, University of the Andes, Santiago, Chile; Cells for Cells, Santiago, Chile, Faculty of Medicine, University of the Andes, Santiago, Chile.
authors.forename: Paz
authors.initials: P
authors.lastname: Gonzalez
authors.affiliation: Laboratory of Integrative and Molecular Physiology, Faculty of Medicine, University of the Andes, Santiago, Chile.
authors.forename: Carlos
authors.initials: C
authors.lastname: Irarrázabal
authors.affiliation: Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile.
authors.forename: Nataly
authors.initials: N
authors.lastname: Quezada
authors.affiliation: Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile.
authors.forename: Fernando
authors.initials: F
authors.lastname: Figueroa
authors.affiliation: Cellular and Molecular Immunology Laboratory, Faculty of Medicine, University of the Andes, Santiago, Chile. Electronic address: fcarrion@uandes.cl.
authors.forename: Flavio
authors.initials: F
authors.lastname: Carrión
mesh_terms: D000818:Animals; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000628:therapy*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000494:pharmacology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014470:Umbilical Cord / Q000166:cytology
chemical_list: D008070:Lipopolysaccharides; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D016264:Dextran Sulfate; D011070:Poly I-C
keywords: cell therapy; dextran sulfate sodium–induced colitis; immunosuppression; inflammatory bowel disease; toll-like receptors; umbilical cord–derived mesenchymal stromal cells