Stem cells for murine interstitial cells of Cajal suppress cellular immunity and colitis via prostaglandin E<inf>2</inf> secretion

Maneesh Dave, Yujiro Hayashi, Gabriella B. Gajdos, Thomas Christopher Smyrk, Phyllis A. Svingen, Sergiy M. Kvasha, Andrea Lorincz, Haidong M Dong, William Alvis Faubion, Tamas Ordog

Research output: Contribution to journalArticle

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Abstract

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 E<inf>2</inf>. 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 E<inf>2</inf>-mediated immunosuppression.

Original languageEnglish (US)
Pages (from-to)978-990
Number of pages13
JournalGastroenterology
Volume148
Issue number5
DOIs
StatePublished - May 1 2015

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Interstitial Cells of Cajal
Colitis
Dinoprostone
Cellular Immunity
Stem Cells
Mesenchymal Stromal Cells
Immunosuppression
T-Lymphocytes
Cell Proliferation
Gene Expression Profiling
Death Domain Receptors
Cyclooxygenase 1
Dextran Sulfate
Mixed Lymphocyte Culture Test
Cyclooxygenase Inhibitors
Homologous Transplantation
Transforming Growth Factors
Regulatory T-Lymphocytes
Cyclooxygenase 2
Inflammatory Bowel Diseases

Keywords

  • IBD
  • ICC
  • Immunosuppression

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Stem cells for murine interstitial cells of Cajal suppress cellular immunity and colitis via prostaglandin E<inf>2</inf> secretion. / Dave, Maneesh; Hayashi, Yujiro; Gajdos, Gabriella B.; Smyrk, Thomas Christopher; Svingen, Phyllis A.; Kvasha, Sergiy M.; Lorincz, Andrea; Dong, Haidong M; Faubion, William Alvis; Ordog, Tamas.

In: Gastroenterology, Vol. 148, No. 5, 01.05.2015, p. 978-990.

Research output: Contribution to journalArticle

Dave, Maneesh ; Hayashi, Yujiro ; Gajdos, Gabriella B. ; Smyrk, Thomas Christopher ; Svingen, Phyllis A. ; Kvasha, Sergiy M. ; Lorincz, Andrea ; Dong, Haidong M ; Faubion, William Alvis ; Ordog, Tamas. / Stem cells for murine interstitial cells of Cajal suppress cellular immunity and colitis via prostaglandin E<inf>2</inf> secretion. In: Gastroenterology. 2015 ; Vol. 148, No. 5. pp. 978-990.
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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 Christopher

AU - Svingen, Phyllis A.

AU - Kvasha, Sergiy M.

AU - Lorincz, Andrea

AU - Dong, Haidong M

AU - Faubion, William Alvis

AU - Ordog, Tamas

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.

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KW - ICC

KW - Immunosuppression

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