Papel do óxido nítrico no transplante alogênico de células mesenquimais estromais na Doença Inflamatória Intestinal

Abstract

1 Inflammatory Bowel Diseases (IBD) are chronic relapsing diseases that result in diarrhea, 2 abdominal pain, rectal bleeding and malnutrition. The inflammation in ulcerative colitis (UC) 3 is restricted to the colonic mucosa, whereas Crohn's disease (CD) is characterized by 4 transmural infiltration that may affect any part of the gastrointestinal tract. CD is 5 characterized by a Th1 response and UC presents an atypical Th2 response, while Th17 is 6 present in elevated levels in inflamed mucosa of both CD and UC. The treatment routinely 7 used in IBD includes various drugs and surgeries; however, no currently available therapy 8 represents the cure for IBD, which may also predispose to colorectal cancer. Then, new 9 therapeutic approaches are necessary for better control of IBD. Mesenchymal stromal cells 10 (MSC) are multipotent cells that have immunoregulatory properties and are therefore 11 considered as important therapeutic tool for various chronic inflammatory diseases, including 12 IBD. These cells suppress the immune response by several mechanisms, such as by the 13 production of nitric oxide (NO) induced by activation of inducible Nitric Oxide Synthase 14 (iNOS). In this context, this study aimed to assess the therapeutic potential of MSC from WT 15 or iNOS-/- mice in IBD. IBD was induced in BALB/c mice by intrarretal enema of 16 trinitrobenzene sulfonic acid (TNBS). Animals were treated with allogeneic MSC derived from 17 the bone marrow of WT or iNOS-/- C57BL/6 mice and were euthanized 3, 7 or 14 days later. 18 The results showed that both MSC showed surface markers and plasticity inherent to this cell 19 type although MSC iNOS-/- were not able to differentiate into osteoblasts. Treated animals 20 had decreased disease clinical signs and increased survival, besides normalization of 21 systemic leukocyte counts and changes in populations of neutrophils and eosinophils in the 22 intestine. Both MSC led to decreased local inflammation and reestablishment of intestinal 23 architecture. However, the local inflammation was differentially modulated by MSC 24 depending on the presence of NO, since WT MSC controlled the Th17 response and led to 25 increased IL-10 levels while the iNOS-/- MSC induced a shift to the Th2 response in the gut. 26 Finally, this study contributed to the elucidation of the mechanisms that mediate the 27 therapeutic potential of MSC in IBD.