title: Stem cells for murine interstitial cells of cajal suppress cellular immunity and colitis via prostaglandin E2 secretion.
abstract: OBJECTIVE
  After allogeneic transplantation, murine stem cells (SCs) for interstitial cells of Cajal (ICCs), electrical pacemaker, and neuromodulator cells of the gut, were incorporated into gastric ICC networks, indicating in vivo immunosuppression. Immunosuppression is characteristic of bone marrow- and other non-gut-derived mesenchymal stem cells (MSCs), which are emerging as potential therapeutic agents against autoimmune diseases, including inflammatory bowel disease. Therefore, we investigated whether gut-derived ICC-SCs could also mitigate experimental colitis and studied the mechanisms of ICC-SC-mediated immunosuppression in relation to MSC-induced pathways.
  
  
  METHODS
  Isolated ICC-SCs were studied by transcriptome profiling, cytokine assays, flow cytometry, mixed lymphocyte reaction, and T-cell proliferation assay. Mice with acute and chronic colitis induced by dextran sulfate sodium and T-cell transfer, respectively, were administered ICC-SCs intraperitoneally and evaluated for disease activity by clinical and pathological assessment and for ICC-SC homing by live imaging.
  
  
  RESULTS
  Unlike strain-matched dermal fibroblasts, intraperitoneally administered ICC-SCs preferentially homed to the colon and reduced the severity of both acute and chronic colitis assessed by clinical and blind pathological scoring. ICC-SCs profoundly suppressed T-cell proliferation in vitro. Similar to MSCs, ICC-SCs strongly expressed cyclooxygenase 1/2 and basally secreted prostaglandin E2. Indomethacin, a cyclooxygenase inhibitor, countered the ICC-SC-mediated suppression of T-cell proliferation. In contrast, we found no role for regulatory T-cell-, programmed death receptor-, and transforming growth factor-β-mediated mechanisms reported in MSCs; and transcriptome profiling did not support a relationship between ICC-SCs and MSCs.
  
  
  CONCLUSIONS
  Murine ICC-SCs belong to a class different from MSCs and potently mitigate experimental colitis via prostaglandin E2-mediated immunosuppression.
authors: Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors: Maneesh
authors: M
authors: Dave
authors: Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors: Yujiro
authors: Y
authors: Hayashi
authors: Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors: Gabriella B
authors: GB
authors: Gajdos
authors: Department of Pathology, Mayo Clinic, Rochester, Minnesota.
authors: Thomas C
authors: TC
authors: Smyrk
authors: Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors: Phyllis A
authors: PA
authors: Svingen
authors: Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors: Sergiy M
authors: SM
authors: Kvasha
authors: Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors: Andrea
authors: A
authors: Lorincz
authors: Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors: Haidong
authors: H
authors: Dong
authors: Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address: faubion.william@mayo.edu.
authors: William A
authors: WA
authors: Faubion
authors: Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address: ordog.tamas@mayo.edu.
authors: Tamas
authors: T
authors: Ordog
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D016264:Dextran Sulfate; D015232:Dinoprostone / Q000378:metabolism*; D020869:Gene Expression Profiling; D005819:Genetic Markers; D018398:Homeodomain Proteins / Q000235:genetics; D007111:Immunity, Cellular; D016867:Immunocompromised Host; D056885:Interstitial Cells of Cajal / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D008213:Lymphocyte Activation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D013997:Time Factors
chemical_list: D004268:DNA-Binding Proteins; D005819:Genetic Markers; D018398:Homeodomain Proteins; C499308:Rag2 protein, mouse; C064658:RAG-1 protein; D016264:Dextran Sulfate; D015232:Dinoprostone
keywords: IBD; ICC; Immunosuppression
references: Nat Protoc. 2007;2(3):541-6
references: 17406617
references: Cytotherapy. 2006;8(4):315-7
references: 16923606
references: Physiol Genomics. 2007 Nov 14;31(3):492-509
references: 17895395
references: FASEB J. 2008 Mar;22(3):659-61
references: 17942826
references: Gastroenterology. 2008 Apr;134(4):1083-93
references: 18395089
references: Nat Med. 2009 Jan;15(1):42-9
references: 19098906
references: Gastroenterology. 2009 Mar;136(3):978-89
references: 19135996
references: Clin Exp Immunol. 2009 Apr;156(1):149-60
references: 19210524
references: Gut. 2009 Jul;58(7):929-39
references: 19136511
references: Gastroenterology. 2009 Nov;137(5):1548-56
references: 19778538
references: PLoS Comput Biol. 2009 Dec;5(12):e1000598
references: 20011106
references: Gastroenterology. 2010 Sep;139(3):942-52
references: 20621681
references: J Biol Chem. 2010 Feb 12;285(7):5026-39
references: 20018844
references: Biochem Biophys Res Commun. 2010 Jan 1;391(1):38-42
references: 19895786
references: Immunity. 2011 Apr 22;34(4):566-78
references: 21511185
references: Immunol Cell Biol. 2012 Jul;90(6):579-86
references: 21946663
references: Cell Mol Life Sci. 2012 Aug;69(15):2593-608
references: 22349262
references: J Biol Chem. 2012 Oct 5;287(41):34372-85
references: 22896699
references: Immunol Cell Biol. 2013 Jan;91(1):19-26
references: 23090487
references: Nat Med. 2013 Jan;19(1):35-42
references: 23296015
references: Gastroenterology. 2013 Dec;145(6):1392-403.e1-8
references: 23973922
references: Clin Gastroenterol Hepatol. 2014 Jan;12(1):64-71
references: 23872668
references: J Biol Chem. 2014 Feb 21;289(8):4571-7
references: 24362036
references: Physiol Rev. 2014 Jul;94(3):859-907
references: 24987007
references: Mol Biol Rep. 2014 Aug;41(8):4977-83
references: 24737572
references: Gastroenterol Clin North Am. 2014 Sep;43(3):405-24
references: 25110250
references: Inflamm Bowel Dis. 2007 Mar;13(3):254-61
references: 17206702
references: Stem Cells. 2002;20(1):41-9
references: 11796921
references: J Clin Invest. 2002 Apr;109(7):883-93
references: 11927615
references: Nat Rev Immunol. 2002 Nov;2(11):859-71
references: 12415309
references: Gastroenterology. 2004 Jun;126(7):1759-70
references: 15188171
references: J Immunol. 1987 Aug 15;139(4):1179-84
references: 3038999
references: J Immunol. 1987 Sep 15;139(6):2075-80
references: 3040863
references: Blood. 1999 Apr 1;93(7):2308-18
references: 10090941
references: Immunity. 2005 Mar;22(3):329-41
references: 15780990
references: Eur J Immunol. 2005 May;35(5):1482-90
references: 15827960