Bone marrow transplantation ameliorates pathology in interleukin-10 knockout colitic mice.

ABSTRACT

The authors have previously reported the derivation of colonic subepithelial myofibroblasts (SEMFs) in both humans and mice from bone marrow (BM). In the pathogenesis of inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis, colonic SEMFs mediate several types of inflammatory response. In the present study, interleukin (IL)-10-/- mice were used as a model of IBD to investigate the involvement of BM-derived cells in the inflamed mucosa. Male whole BM [either C57/BL10 (wild type WT) or IL-10-/- donor mice] was used to perform bone marrow transplantation (BMT) into both WT and IL-10-/- female mice. Tissue samples were evaluated by immunohistochemistry for alpha-smooth muscle actin expression and by in situ hybridization using a Y-chromosome-specific probe to track the donor-derived colonic SEMFs. The mucosal expression of mRNA for pro-inflammatory cytokines was analysed by reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, mRNA expression of matrix metalloproteinase (MMP)-7 and osteopontin in the inflamed mucosa was assessed using in situ hybridization. Body weights and histological scores showed that IL-10-/- mice that received WT BM had an improved course of colitis, decreased mucosal pro-inflammatory mRNA expression, and up to 30% of their SEMFs were of BM origin. Conversely, IL-10-/- mice receiving IL-10-/- BM progressed to extensive colitis, and Y probe analysis revealed that up to 45% of colonic SEMFs were of BM origin. WT mice receiving IL-10-/- or WT BM had no signs of colonic inflammation. The expression of MMP-7 and osteopontin was up-regulated in the inflamed mucosa. In conclusion, IL-10-/- mice displayed ameliorated disease activity after WT BMT, whilst colitis was not induced in WT mice by IL-10-/- BMT. The contribution of BM-derived cells to colonic SEMFs was significantly increased in the inflamed mucosa compared with non-inflamed mucosa.