Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2

Hyung Sik Kim, Tae Hoon Shin, Byung Chul Lee, Kyung Rok Yu, Yoojin Seo, Seunghee Lee, Min Soo Seo, In Sun Hong, Soon Won Choi, Kwang Won Seo, Gabriel Núñez, Jong Hwan Park, Kyung Sun Kang

Research output: Contribution to journalArticlepeer-review

153 Scopus citations

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.

Original languageEnglish
Pages (from-to)1392-1403.e8
JournalGastroenterology
Volume145
Issue number6
DOIs
StatePublished - Dec 2013

Keywords

  • IBD
  • Immune Regulation
  • Mouse Model
  • Signal Transduction

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