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Generation of Novel IL-10 Mesenchymal Stem/Stromal Cells

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Generation of Novel IL-10 Mesenchymal Stem/Stromal Cells Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IL-10 −Dependent Regulatory Dendritic Cells by SOCS3 Activation This information is current as of October 3, 2021. Xingxia Liu, Xuebin Qu, Yuan Chen, Lianming Liao, Kai Cheng, Changshun Shao, Martin Zenke, Armand Keating and Robert C. H. Zhao J Immunol 2012; 189:1182-1192; Prepublished online 2 July 2012; Downloaded from doi: 10.4049/jimmunol.1102996 http://www.jimmunol.org/content/189/3/1182 Supplementary http://www.jimmunol.org/content/suppl/2012/07/02/jimmunol.110299 http://www.jimmunol.org/ Material 6.DC1 References This article cites 50 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/189/3/1182.full#ref-list-1 Why The JI? Submit online. by guest on October 3, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IL-10–Dependent Regulatory Dendritic Cells by SOCS3 Activation Xingxia Liu,*,1 Xuebin Qu,*,1 Yuan Chen,* Lianming Liao,† Kai Cheng,* Changshun Shao,‡ Martin Zenke,x Armand Keating,{,‖,# and Robert C. H. Zhao* Suppression of immune response by mesenchymal stem/stromal cells (MSCs) is well documented. However, their regulatory effects on immune cells, especially regulatory dendritic cells, are not fully understood. We have identified a novel Sca-1+Lin2CD1172 MSC population isolated from mouse embryonic fibroblasts (MEF) that suppressed lymphocyte proliferation in vitro. Moreover, the Sca-1+Lin2CD1172 MEF-MSCs induced hematopoietic stem/progenitor cells to differentiate into novel regulatory dendritic cells (DCs) (Sca-1+Lin2CD1172 MEF-MSC–induced DCs) when cocultured in the absence of exogenous cytokines. Small interfering RNA silencing showed that Sca-1+Lin2CD1172 MEF-MSCs induced the generation of Sca-1+Lin2CD1172 MEF-MSC–induced Downloaded from DCs via IL-10–activated SOCS3, whose expression was regulated by the JAK–STAT pathway. We observed a high degree of H3K4me3 modification mediated by MLL1 and a relatively low degree of H3K27me3 modification regulated by SUZ12 on the promoter of SOCS3 during SOCS3 activation. Importantly, infusion of Sca-1+CD1172Lin2 MEF-MSCs suppressed the inflam- matory response by increasing DCs with a regulatory phenotype. Thus, our results shed new light on the role of MSCs in modulating regulatory DC production and support the clinical application of MSCs to reduce the inflammatory response in numerous disease states. The Journal of Immunology, 2012, 189: 1182–1192. http://www.jimmunol.org/ esenchymal stem/stromal cells (MSCs), capable of DCs, especially regulatory DCs (regDCs), are key regulators of multilineage differentiation (1, 2), are weakly immu- immune responses. Several types of regDCs, with similar functions M nogenic and possess immune regulatory properties (3– but different phenotypes (13–18), can be induced by a cytokine 5). Previous studies have shown that bone marrow-derived MSCs mixture that includes GM-CSF, IL-10, and TGF-b in vitro; how- (BM-MSCs) can secrete inhibitory cytokines, suppress T cell ever, these induction conditions do not accurately mimic the mi- activation and proliferation, and regulate dendritic cell (DC) croenvironment in vivo, which involves a complex orchestration by guest on October 3, 2021 functions (6–9). In vivo, MSCs can prevent and treat graft-versus- and regulation of cytokine production and cell-cell interaction. host disease by suppressing Th1 lymphocyte function (10), at- Previous reports showed that BM-MSCs could influence DC dif- tenuate the pathological manifestations of experimental autoim- ferentiation (8, 9), and Cao’s group (19) showed that endothelial mune encephalomyelitis via regulatory T cell expansion and splenic stroma could induce the differentiation of CD11bhighIalow proinflammatory Th17 cell depression (11), and inhibit B cell regDCs from bone marrow hematopoietic stem/progenitor cells activation, proliferation, and IgG secretion in systemic lupus (BM-HPCs), but the induction of regDCs in vivo remains con- erythematosus (12). Although MSCs can regulate T and B immune troversial. cells via many mechanisms, relatively little is known about the Recent data support the concept that specific gene expression effects of MSCs on DC function. patterns that determine the behavior of individual cells are under *Institute of Basic Medical Sciences and School of Basic Medicine, Center of Excel- and Project of Institute of Basic Medical Sciences of Chinese Academy of Medical lence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Sciences Grant 2008PY09. Medical College, Beijing 100005, People’s Republic of China; †Academy of Integra- Address correspondence and reprint requests to Prof. Robert C.H. Zhao or Dr. tive Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350108, Armand Keating, Institute of Basic Medical Sciences and School of Basic Medicine, Fujian, People’s Republic of China; ‡Department of Genetics, Rutgers, The State x Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences University of New Jersey, Piscataway, NJ 08854; Department of Cell Biology, Insti- and Peking Union Medical College, 5 Dongdansantiao, Beijing 100005, People’s tute for Biomedical Engineering, Rhenish-Westphalian Technical University, Aachen { Republic of China (R.C.H.Z.) or Cell Therapy Program, Princess Margaret Hospital, University Medical School, 52074 Aachen, Germany; Cell Therapy Program, Prin- ‖ 610 University Avenue, Toronto, Ontario M5G 2M9, Canada (A.K.). E-mail cess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada; Institute of Biomate- addresses: [email protected] (R.C.H.Z.) and [email protected] (A.K.) rials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5G 2M9, Canada; and #Institute of Medical Science, University of Toronto, Toronto, The online version of this article contains supplemental material. Ontario M5G 2M9, Canada Abbreviations used in this article: BM-HPC, bone marrow hematopoietic stem/ 1X.L. and X.Q. contributed equally to this work. progenitor cell; BM-MSC, bone marrow-derived mesenchymal stem/stromal cell; ChIP, chromatin immunoprecipitation; DC, dendritic cell; HPC, hematopoietic Received for publication October 17, 2011. Accepted for publication May 23, 2012. stem/progenitor cell; imDC, immature DC; maDC, mature DC; MEF, mouse embry- This work was supported by “863 Projects” of Ministry of Science and Technology of onic fibroblast; MSC, mesenchymal stem/stromal cell; NA, neutralizing Ab; NS, People’s Republic of China Grant 2006AA02A109; National Natural Science Foun- normal saline; PCA, principal components analysis; qRT-PCR, quantitative RT- 2 2 dation of China Grants 30830052, 30700321, 30800429, and 30911130363; Beijing PCR; regDC, regulatory DC; sDC, Sca-1+Lin CD117 MEF-MSC–induced DC; Ministry of Science and Technology Grant D07050701350701; Major National siRNA, small interfering RNA. Science and Technology Project Grants 2008ZX09101-044 and 2009ZX09503-025; National Key Scientific Program of China Grant 2011CB964900; Program for Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 Changjiang Scholars and Innovative Research Team in University Grant IRT0909; www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102996 The Journal of Immunology 1183 the control of epigenetic alterations, including histone mod- Coculture experiment ifications. Methylation of the histone lysines, H3K4 and H3K27, HPCs were enriched from bone marrow cells by depleting lineage-specific mediated by distinct histone methyltransferase complexes, is cells. In brief, an EasySep mouse hematopoietic progenitor enrichment kit highly correlated with transcriptional activation or repression (20, (StemCell Technologies) was used to deplete lineage-specific cells. After + 2 2 21). A growing body of evidence has shown that epigenetic HPCs were purified, they were seeded onto Sca-1 CD117 Lin mono- 3 5 alterations are involved in the regulation of various genes layers at a density of 1 10 in 2 ml per well in 6-well plates. The ratio of MSC/HPC is 1:10. LPS was added on day 4. In some experiments, expressed during normal embryonic development, stem cell dif- a neutralizing Ab (NA) for IL-10 (10 mg/ml) was added every 2 d; 100 mM ferentiation, cancer growth, and autoimmune disease progress (22, NSC 74859 (a phospho-STAT3 inhibitor; Merck) or 10 mM CGP 41251 (a 23). Histone methylation has also been implicated in the devel- phospho-STAT5 inhibitor; Merck) was used for 24 or 48 h, respectively; opment of immune responses, especially in the production of IL- serum replacement (StemCell Technologies) was used to substitute for serum. After coculture on Sca-1+CD1172Lin2 feeder layers for 9
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