Background & Aims
Following allogeneic transplantation, murine stem cells (SC) for interstitial cells of Cajal (ICC), electrical pacemaker and neuromodulator cells of the gut, incorporated into gastric ICC networks indicating in-vivo immunosuppression. Immunosuppression is characteristic of bone marrow- and other non-gut-derived mesenchymal stem cells (MSC), which are emerging as potential therapeutic agents against autoimmune diseases including inflammatory bowel disease. Therefore, we investigated whether gut-derived ICC-SC could also mitigate experimental colitis and studied the mechanisms of ICC-SC-mediated immunosuppression in relation to MSC-induced pathways.
Isolated ICC-SC 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-SC intraperitoneally and evaluated for disease activity by clinical and pathological assessment and for ICC-SC homing by live imaging.
Unlike strain-matched dermal fibroblasts, intraperitoneally administered ICC-SC preferentially homed to the colon and reduced the severity of both acute and chronic colitis assessed by clinical and blind pathological scoring. ICC-SC profoundly suppressed T cell proliferation in vitro. Similarly to MSC, ICC-SC 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 MSC; and transcriptome profiling did not support a relationship between ICC-SC and MSC.
Murine ICC-SC belong to a class different from MSC and potently mitigate experimental colitis via prostaglandin E2-mediated immunosuppression.