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Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2.
Gastroenterology 2013; 145(6):1392-403.e1-8G

Abstract

BACKGROUND & AIMS

Decreased levels or function of nucleotide-binding oligomerization domain 2 (NOD2) are associated with Crohn's disease. NOD2 regulates intestinal inflammation, and also is expressed by human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs), to regulate their differentiation. We investigated whether NOD2 is required for the anti-inflammatory activities of MSCs in mice with colitis.

METHODS

Colitis was induced in mice by administration of dextran sulfate sodium or trinitrobenzene sulfonic acid. Mice then were given intraperitoneal injections of NOD2-activated hUCB-MSCs; colon tissues and mesenteric lymph nodes were collected for histologic analyses. A bromodeoxyuridine assay was used to determine the ability of hUCB-MSCs to inhibit proliferation of human mononuclear cells in culture.

RESULTS

Administration of hUCB-MSCs reduced the severity of colitis in mice. The anti-inflammatory effects of hUCB-MSCs were greatly increased by activation of NOD2 by its ligand, muramyl dipeptide (MDP). Administration of NOD2-activated hUCB-MSCs increased anti-inflammatory responses in colons of mice, such as production of interleukin (IL)-10 and infiltration by T regulatory cells, and reduced production of inflammatory cytokines. Proliferation of mononuclear cells was inhibited significantly by co-culture with hUCB-MSCs that had been stimulated with MDP. MDP induced prolonged production of prostaglandin (PG)E2 in hUCB-MSCs via the NOD2-RIP2 pathway, which suppressed proliferation of mononuclear cells derived from hUCB. PGE2 produced by hUCB-MSCs in response to MDP increased production of IL-10 and T regulatory cells. In mice, production of PGE2 by MSCs and subsequent production of IL-10 were required to reduce the severity of colitis.

CONCLUSIONS

Activation of NOD2 is required for the ability of hUCB-MSCs to reduce the severity of colitis in mice. NOD2 signaling increases the ability of these cells to suppress mononuclear cell proliferation by inducing production of PGE2.

Authors+Show Affiliations

Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23973922

Citation

Kim, Hyung-Sik, et al. "Human Umbilical Cord Blood Mesenchymal Stem Cells Reduce Colitis in Mice By Activating NOD2 Signaling to COX2." Gastroenterology, vol. 145, no. 6, 2013, pp. 1392-403.e1-8.
Kim HS, Shin TH, Lee BC, et al. Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2. Gastroenterology. 2013;145(6):1392-403.e1-8.
Kim, H. S., Shin, T. H., Lee, B. C., Yu, K. R., Seo, Y., Lee, S., ... Kang, K. S. (2013). Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2. Gastroenterology, 145(6), pp. 1392-403.e1-8. doi:10.1053/j.gastro.2013.08.033.
Kim HS, et al. Human Umbilical Cord Blood Mesenchymal Stem Cells Reduce Colitis in Mice By Activating NOD2 Signaling to COX2. Gastroenterology. 2013;145(6):1392-403.e1-8. PubMed PMID: 23973922.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2. AU - Kim,Hyung-Sik, AU - Shin,Tae-Hoon, AU - Lee,Byung-Chul, AU - Yu,Kyung-Rok, AU - Seo,Yoojin, AU - Lee,Seunghee, AU - Seo,Min-Soo, AU - Hong,In-Sun, AU - Choi,Soon Won, AU - Seo,Kwang-Won, AU - Núñez,Gabriel, AU - Park,Jong-Hwan, AU - Kang,Kyung-Sun, Y1 - 2013/08/21/ PY - 2012/11/16/received PY - 2013/08/14/revised PY - 2013/08/15/accepted PY - 2013/8/27/entrez PY - 2013/8/27/pubmed PY - 2014/2/25/medline KW - 5,6-carboxy fluorescein succinimidyl ester KW - CFSE KW - CM KW - COX-2 KW - DSS KW - Foxp3 KW - IBD KW - IDO-1 KW - IFN KW - IL KW - Immune Regulation KW - LPS KW - MDP KW - MLN KW - MLR KW - MNC KW - MPO KW - Mouse Model KW - NF-κB KW - NO KW - NOD2 KW - PBS KW - PG KW - RIP KW - Signal Transduction KW - T-helper cell KW - TLR KW - TNBS KW - TNF KW - Th KW - Toll-like receptor KW - Treg KW - UCM KW - culture media KW - cyclooxygenase-2 KW - dextran sulfate sodium KW - forkhead box p3 KW - hMNC KW - hUCB-MSCs KW - human mononuclear cell KW - human umbilical cord blood-derived mesenchymal stem cells KW - indoleamine-2,3-dioxygenase-1 KW - interferon KW - interleukin KW - lipopolysaccharide KW - mesenteric lymph node KW - mixed lymphocyte reaction KW - mononuclear cell KW - muramyl dipeptide KW - myeloperoxidase KW - nitric oxide KW - nuclear factor-κB KW - nucleotide-binding oligomerization domain 2 KW - phosphate-buffered saline KW - prostaglandin KW - receptor-interacting protein KW - regulatory T cell KW - siRNA KW - small interfering RNA KW - trinitrobenzene sulfonic acid KW - tumor necrosis factor KW - umbilical cord blood-derived mesenchymal stem cell conditioned medium SP - 1392-403.e1-8 JF - Gastroenterology JO - Gastroenterology VL - 145 IS - 6 N2 - BACKGROUND & AIMS: Decreased levels or function of nucleotide-binding oligomerization domain 2 (NOD2) are associated with Crohn's disease. NOD2 regulates intestinal inflammation, and also is expressed by human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs), to regulate their differentiation. We investigated whether NOD2 is required for the anti-inflammatory activities of MSCs in mice with colitis. METHODS: Colitis was induced in mice by administration of dextran sulfate sodium or trinitrobenzene sulfonic acid. Mice then were given intraperitoneal injections of NOD2-activated hUCB-MSCs; colon tissues and mesenteric lymph nodes were collected for histologic analyses. A bromodeoxyuridine assay was used to determine the ability of hUCB-MSCs to inhibit proliferation of human mononuclear cells in culture. RESULTS: Administration of hUCB-MSCs reduced the severity of colitis in mice. The anti-inflammatory effects of hUCB-MSCs were greatly increased by activation of NOD2 by its ligand, muramyl dipeptide (MDP). Administration of NOD2-activated hUCB-MSCs increased anti-inflammatory responses in colons of mice, such as production of interleukin (IL)-10 and infiltration by T regulatory cells, and reduced production of inflammatory cytokines. Proliferation of mononuclear cells was inhibited significantly by co-culture with hUCB-MSCs that had been stimulated with MDP. MDP induced prolonged production of prostaglandin (PG)E2 in hUCB-MSCs via the NOD2-RIP2 pathway, which suppressed proliferation of mononuclear cells derived from hUCB. PGE2 produced by hUCB-MSCs in response to MDP increased production of IL-10 and T regulatory cells. In mice, production of PGE2 by MSCs and subsequent production of IL-10 were required to reduce the severity of colitis. CONCLUSIONS: Activation of NOD2 is required for the ability of hUCB-MSCs to reduce the severity of colitis in mice. NOD2 signaling increases the ability of these cells to suppress mononuclear cell proliferation by inducing production of PGE2. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/23973922/Human_umbilical_cord_blood_mesenchymal_stem_cells_reduce_colitis_in_mice_by_activating_NOD2_signaling_to_COX2_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(13)01226-2 DB - PRIME DP - Unbound Medicine ER -