title: Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2.
abstract: OBJECTIVE
  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: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
authors: Hyung-Sik
authors: HS
authors: Kim
authors: Tae-Hoon
authors: TH
authors: Shin
authors: Byung-Chul
authors: BC
authors: Lee
authors: Kyung-Rok
authors: KR
authors: Yu
authors: Yoojin
authors: Y
authors: Seo
authors: Seunghee
authors: S
authors: Lee
authors: Min-Soo
authors: MS
authors: Seo
authors: In-Sun
authors: IS
authors: Hong
authors: Soon Won
authors: SW
authors: Choi
authors: Kwang-Won
authors: KW
authors: Seo
authors: Gabriel
authors: G
authors: Núñez
authors: Jong-Hwan
authors: JH
authors: Park
authors: Kyung-Sun
authors: KS
authors: Kang
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology / Q000628:therapy*; D051546:Cyclooxygenase 2 / Q000502:physiology*; D016264:Dextran Sulfate / Q000009:adverse effects; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D005312:Fetal Blood / Q000166:cytology*; D006801:Humans; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D016753:Interleukin-10; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D016264:Dextran Sulfate; D051546:Cyclooxygenase 2; D015232:Dinoprostone
keywords: 5,6-carboxy fluorescein succinimidyl ester; CFSE; CM; COX-2; DSS; Foxp3; IBD; IDO-1; IFN; IL; Immune Regulation; LPS; MDP; MLN; MLR; MNC; MPO; Mouse Model; NF-κB; NO; NOD2; PBS; PG; RIP; Signal Transduction; T-helper cell; TLR; TNBS; TNF; Th; Toll-like receptor; Treg; UCM; culture media; cyclooxygenase-2; dextran sulfate sodium; forkhead box p3; hMNC; hUCB-MSCs; human mononuclear cell; human umbilical cord blood-derived mesenchymal stem cells; indoleamine-2,3-dioxygenase-1; interferon; interleukin; lipopolysaccharide; mesenteric lymph node; mixed lymphocyte reaction; mononuclear cell; muramyl dipeptide; myeloperoxidase; nitric oxide; nuclear factor-κB; nucleotide-binding oligomerization domain 2; phosphate-buffered saline; prostaglandin; receptor-interacting protein; regulatory T cell; siRNA; small interfering RNA; trinitrobenzene sulfonic acid; tumor necrosis factor; umbilical cord blood-derived mesenchymal stem cell conditioned medium