TY - JOUR
T1 - Stem cells for murine interstitial cells of Cajal suppress cellular immunity and colitis via prostaglandin E2 secretion
AU - Dave, Maneesh
AU - Hayashi, Yujiro
AU - Gajdos, Gabriella B.
AU - Smyrk, Thomas C.
AU - Svingen, Phyllis A.
AU - Kvasha, Sergiy M.
AU - Lorincz, Andrea
AU - Dong, Haidong
AU - Faubion, William A.
AU - Ordog, Tamas
N1 - Publisher Copyright:
© 2015 AGA Institute.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - Background & Aims 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.
AB - Background & Aims 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.
KW - IBD
KW - ICC
KW - Immunosuppression
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U2 - 10.1053/j.gastro.2015.01.036
DO - 10.1053/j.gastro.2015.01.036
M3 - Article
C2 - 25637652
AN - SCOPUS:84928699966
SN - 0016-5085
VL - 148
SP - 978
EP - 990
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -