title: TLR3 preconditioning enhances the therapeutic efficacy of umbilical cord mesenchymal stem cells in TNBS-induced colitis via the TLR3-Jagged-1-Notch-1 pathway.
abstract: Toll-like receptor-3 (TLR3) priming may enhance mesenchymal stem cell (MSC) immunosuppressive activity, but this mechanism has not been investigated in the context of inflammatory bowel disease. Thus, we assessed the immunosuppressive properties of TLR3-primed MSCs using a trinitrobenzene sulfonate (TNBS)-induced mouse model of colitis. Intraperitoneally injected polyribocytidylic acid (poly (I:C)- (a ligand of TLR3) primed human umbilical cord-derived MSCs (hUC-MSCs) migrated to the inflamed colon and effectively improved clinical and pathological manifestations in colitic mice compared with mice treated with unstimulated hUC-MSCs (UCMs). Poly (I:C)-MSCs decreased a wide range of inflammatory cytokines and increased systemic interleukin-10 (IL-10) levels in colonic tissues. Poly (I:C)-MSCs also impaired T-helper type 1/17 (Th1/17) cell expansion and enhanced the suppressive effects of regulatory T cells (Treg) in vitro and in vivo. Poly (I:C)-MSCs suppressed the proliferation of activated mesenteric lymph node (MLN) cells via the overproduction of prostaglandin E2(PGE2) and upregulation of Jagged-1. PGE2produced by hUC-MSCs in response to poly (I:C) increased the production of IL-10 and promoted the differentiation of Treg, which could be reversed by inhibition of Notch-1. Collectively, preconditioning MSCs with poly (I:C) enhanced the therapeutic effects of hUC-MSCs in TNBS-induced colitis, and TLR3-activated Notch-1 signaling regulated the immune suppression of hUC-MSCs through the production of PGE2.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: R
authors.initials: R
authors.lastname: Mao
authors.affiliation: Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: K
authors.initials: K
authors.lastname: Chao
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: B-L
authors.initials: BL
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Z-R
authors.initials: ZR
authors.lastname: Zeng
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: S-H
authors.initials: SH
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: M-H
authors.initials: MH
authors.lastname: Chen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007108:Immune Tolerance; D000072100:Jagged-1 Protein / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011070:Poly I-C / Q000276:immunology; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000276:immunology / Q000378:metabolism*; D019172:Transplantation Conditioning; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014470:Umbilical Cord / Q000166:cytology*
chemical_list: D000072100:Jagged-1 Protein; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D014302:Trinitrobenzenesulfonic Acid; D011070:Poly I-C