title: Notch-RBP-J signaling is required by bone marrow stromal cells for the treatment of acute graft versus host disease.
abstract: Recent evidence has shown that bone marrow stromal cells (BMSCs) may exhibit immuno-suppression activities through soluble mediators and direct cell-cell contact, but how these processes are modulated has been poorly understood. In this study, we show that the Notch signaling pathway participates in the modulation of BMSCs to elicit their immuno-suppressive roles. In a murine lethal acute graft versus host disease (aGvHD) model, BMSCs deficient for RBP-J, the critical transcription factor mediating signaling from all four mammalian Notch receptors, failed to delay the development of the disease. RBP-J deficient BMSCs were not able to inhibit the proliferation and activation of allogenic T-cells. Moreover, RBP-J deficient BMSCs could not down-regulate the expression of MHC II and co-stimulation molecules CD80 and CD86 on dendritic cells (DCs). The antigen presentation capacity of DCs co-cultured with RBP-J deficient BMSCs was not impaired in contrast to wild type BMSCs. Furthermore, we showed that the productions of IL-6 and PGE2, two critical molecules mediating the immuno-suppressive activities of BMSCs, were reduced significantly in RBP-J deficient BMSCs. Both of the two molecules were importantly involved in the regulation of BMSCs by Notch signaling. In conclusion, our data suggests that the immuno-suppressive effects of BMSCs in aGvHD are dependent on Notch-RBP-J signaling, which regulates the productions of IL-6 and PGE2.
authors.affiliation: Center for Cell Therapy and Research, General Hospital of Guangzhou Military Command of PLA, Guangzhou 510010, China.
authors.forename: Yao-Chun
authors.initials: YC
authors.lastname: Wang
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Wang
authors.forename: Ya-Ning
authors.initials: YN
authors.lastname: Wei
authors.forename: De-Wei
authors.initials: DW
authors.lastname: Du
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.forename: Chun-Chen
authors.initials: CC
authors.lastname: Gao
authors.forename: Min-Hua
authors.initials: MH
authors.lastname: Zheng
authors.forename: Juan
authors.initials: J
authors.lastname: Xie
authors.forename: Jun-Chang
authors.initials: JC
authors.lastname: Li
authors.forename: Guang-Ying
authors.initials: GY
authors.lastname: Dong
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.forename: Hua
authors.initials: H
authors.lastname: Han
mesh_terms: D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000378:metabolism / Q000628:therapy*; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D051880:Receptors, Notch