title: Sca-1+Lin-CD117- mesenchymal stem/stromal cells induce the generation of novel IRF8-controlled regulatory dendritic cells through Notch-RBP-J signaling.
abstract: Mesenchymal stem/stromal cells (MSCs) can influence the destiny of hematopoietic stem/progenitor cells (HSCs) and exert broadly immunomodulatory effects on immune cells. However, how MSCs regulate the differentiation of regulatory dendritic cells (regDCs) from HSCs remains incompletely understood. In this study, we show that mouse bone marrow-derived Sca-1(+)Lin(-)CD117(-) MSCs can drive HSCs to differentiate into a novel IFN regulatory factor (IRF)8-controlled regDC population (Sca(+) BM-MSC-driven DC [sBM-DCs]) when cocultured without exogenous cytokines. The Notch pathway plays a critical role in the generation of the sBM-DCs by controlling IRF8 expression in an RBP-J-dependent way. We observed a high level of H3K27me3 methylation and a low level of H3K4me3 methylation at the Irf8 promoter during sBM-DC induction. Importantly, infusion of sBM-DCs could alleviate colitis in mice with inflammatory bowel disease by inhibiting lymphocyte proliferation and increasing the numbers of CD4(+)CD25(+) regulatory T cells. Thus, these data infer a possible mechanism for the development of regDCs and further support the role of MSCs in treating immune disorders.
authors.affiliation: Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100005, People's Republic of China;
authors.forename: Xingxia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100005, People's Republic of China;
authors.forename: Shaoda
authors.initials: S
authors.lastname: Ren
authors.affiliation: Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100005, People's Republic of China;
authors.forename: Chaozhuo
authors.initials: C
authors.lastname: Ge
authors.affiliation: Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100005, People's Republic of China;
authors.forename: Kai
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Department of Cell Biology, Institute for Biomedical Engineering, Rhenish-Westphalian Technical University, Aachen University Medical School, 52074 Aachen, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Zenke
authors.affiliation: Cell Therapy Program, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada; and Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Armand
authors.initials: A
authors.lastname: Keating
authors.affiliation: Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100005, People's Republic of China; zhaochunhua@vip.163.com.
authors.forename: Robert C H
authors.initials: RC
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D006657:Histones / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism*; D056747:Immunomodulation; D018836:Inflammation Mediators / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D000099185:Interferon Regulatory Factor-8
chemical_list: D000950:Antigens, Ly; D016207:Cytokines; D006657:Histones; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D018836:Inflammation Mediators; D050835:Interferon Regulatory Factors; D008565:Membrane Proteins; D019009:Proto-Oncogene Proteins c-kit; D051880:Receptors, Notch; D000099185:Interferon Regulatory Factor-8; C074650:Ly6a protein, mouse; C497571:Rbpj protein, mouse