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Immunogenic Dendritic Cell Generation from Pluripotent Stem Cells by Ectopic Expression of Runx3

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Immunogenic Dendritic Cell Generation from Pluripotent Stem Cells by Ectopic Expression of Runx3 Immunogenic Dendritic Cell Generation from Pluripotent Stem Cells by Ectopic Expression of Runx3 This information is current as Erika Takacs, Pal Boto, Emilia Simo, Tamas I. Csuth, of September 25, 2021. Bianka M. Toth, Hadas Raveh-Amit, Attila Pap, Elek G. Kovács, Julianna Kobolak, Szilvia Benkö, Andras Dinnyes and Istvan Szatmari J Immunol published online 16 November 2016 http://www.jimmunol.org/content/early/2016/11/15/jimmun Downloaded from ol.1600034 Supplementary http://www.jimmunol.org/content/suppl/2016/11/15/jimmunol.160003 Material 4.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • 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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 16, 2016, doi:10.4049/jimmunol.1600034 The Journal of Immunology Immunogenic Dendritic Cell Generation from Pluripotent Stem Cells by Ectopic Expression of Runx3 Erika Takacs,*,1 Pal Boto,*,1 Emilia Simo,* Tamas I. Csuth,* Bianka M. Toth,* Hadas Raveh-Amit,† Attila Pap,‡ Elek G. Kova´cs,x Julianna Kobolak,† Szilvia Benko¨,x Andras Dinnyes,†,{ and Istvan Szatmari*,‖ Application of dendritic cells (DCs) to prime responses to tumor Ags provides a promising approach to immunotherapy. However, only a limited number of DCs can be manufactured from adult precursors. In contrast, pluripotent embryonic stem (ES) cells represent an inexhaustible source for DC production, although it remains a major challenge to steer directional differentiation because ES cell–derived cells are typically immature with impaired functional capacity. Consistent with this notion, we found that mouse ES cell–derived DCs (ES-DCs) represented less mature cells compared with bone marrow–derived DCs. This finding prompted us to compare the gene expression profile of the ES cell– and adult progenitor-derived, GM-CSF–instructed, noncon- Downloaded from ventional DC subsets. We quantified the mRNA level of 17 DC-specific transcription factors and observed that 3 transcriptional regulators (Irf4, Spi-B, and Runx3) showed lower expression in ES-DCs than in bone marrow–derived DCs. In light of this altered gene expression, we probed the effects of these transcription factors in developing mouse ES-DCs with an isogenic expression screen. Our analysis revealed that forced expression of Irf4 repressed ES-DC development, whereas, in contrast, Runx3 improved the ES-DC maturation capacity. Moreover, LPS-treated and Runx3-activated ES-DCs exhibited enhanced T cell activation and migratory potential. In summary, we found that ex vivo–generated ES-DCs had a compromised maturation ability and immu- http://www.jimmunol.org/ nogenicity. However, ectopic expression of Runx3 enhances cytokine-driven ES-DC development and acts as an instructive tool for the generation of mature DCs with enhanced immunogenicity from pluripotent stem cells. The Journal of Immunology, 2017, 198: 000–000. luripotent stem cells (PSCs), including embryonic stem differentiation capacity. PSC-derived functional cells can be (ES) cells and induced PSCs cells, provide an inexhaustible generated through directed differentiation using well-defined source for cell replacement and adoptive immune cell protocols (1). However, it is still challenging to steer the differ- P by guest on September 25, 2021 therapy because of their unlimited self-renewal activity and broad entiation of PSCs to adult-like cells because the end products often represent embryonic-type or immature cells with limited activity. For example, human ES cell–derived RBCs readily *Stem Cell Differentiation Laboratory, Department of Biochemistry and Molecular expressed the embryonic and fetal globins (ε and g), but the adult Biology, Faculty of Medicine, University of Debrecen, H-4010 Debrecen, Hungary; †Biotalentum Ltd., H-2100 Go¨do¨llo,} Hungary; ‡Department of Biochemistry and b-globin protein was barely detected in these cells (2). Similarly, Molecular Biology, Faculty of Medicine, University of Debrecen, H-4012 Debrecen, the gene expression signature of PSC-derived insulin-producing Hungary; xDepartment of Physiology, Faculty of Medicine, University of Debrecen, { cells mimicked that of fetal pancreatic tissue rather than the adult H-4010 Debrecen, Hungary; Molecular Animal Biotechnology Laboratory, Szent ‖ Istva´n University, H-2101 Go¨do¨llo,} Hungary; and Faculty of Pharmacy, University b cells (3). In addition, immaturity of the sarcoplasmic reticulum of Debrecen, H-4032 Debrecen, Hungary and diminished inotropic response to hormonal stimuli were de- 1E.T. and P.B. are cofirst authors. tected in murine ES cell– or induced PSC–derived cardiac cells ORCIDs: 0000-0002-8780-5199 (P.B.); 0000-0003-3300-8597 (H.R.-A.); 0000- (4). These findings suggest that embryonic developmental pro- 0001-7356-6345 (S.B.); 0000-0003-3791-2583 (A.D.). grams are readily activated in PSC-derived ex vivo–differentiated Received for publication January 6, 2016. Accepted for publication October 28, cells; however, these regulatory networks usually do not guarantee 2016. the production of fully active mature cells. For proper maturation, This work was supported by the University of Debrecen Faculty of Medicine Re- further steps are needed that are unknown or missing from the search Fund (Bridging Fund), Projects TA´ MOP-4.2.1/B-09/1/KONV-2010-0007 and TA´ MOP 4.2.2.A-11/1/KONV-2012–0023 (to I.S.), Project TA´ MOP-4.2.2/B-10/1- existing standard in vitro–differentiation protocols. 2010-0024 (to E.T.), EU FP7 Projects (EpiHealthNet, PITN-GA-2012-317146, IDP- Cell differentiation and commitment are governed by lineage- byNMR, PITN-GA-2010-264257), Research Center of Excellence Project 11476-3/ determining and stimulus-activated transcription factors (5). These 2016/FEKUT (to A.D.), and by Project OTKA K109429 (to S.B.). I.S. and S.B. were the recipients of a Bolyai Fellowship from the Hungarian Academy of Sciences. S.B. master regulators are gradually induced during the embryonic also was the recipient of a Ja´nos Szodoray Postdoctoral Fellowship from the Faculty development, and distinct factors modulate cell fate specification of Medicine, University of Debrecen. during the various stages of differentiation. In this study, we ex- Address correspondence and reprint requests to Dr. Istvan Szatmari, Department of amined the transcription factor network in stem cell–derived dif- Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, Debrecen, H-4010, Hungary. E-mail address: [email protected] ferentiated immune cells. GM-CSF–dependent dendritic cell (DC) The online version of this article contains supplemental material. development was selected as a differentiation model because this Abbreviations used in this article: BM, bone marrow; BM-DC, BM-derived DC; DC, cell type can be generated from adult stem cells and ES cells (6– dendritic cell; ES, embryonic stem; ES-DC, ES cell–derived DC; FSC, forward 13). Moreover, numerous transcription factors were described that scatter; MHCII, MHC class II; pDC, plasmacytoid dendritic cell; PSC, pluripotent control the commitment and specification of DCs (14, 15). In stem cell. addition, in vitro–generated DCs were applied in cell therapy– Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 based clinical trials to provoke anticancer immune responses (16). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600034 2 Runx3-INSTRUCTED DENDRITIC CELLS Therefore, ex vivo DC manufacturing has an immediate biotech- T cell–proliferation analysis nological application. DC generation from PSCs is a promising Splenic T cells were isolated and purified from male BALB/c mice using a approach; however, PSC-derived DCs often exhibited a subopti- Pan T Cell Isolation Kit II (Miltenyi Biotec, Bergisch Gladbach, Germany). mal T cell–activation capacity (6, 11, 13). Consistent with this The purified T cells were used as responders. For allogeneic MLRs, 103 or 4 5 notion, in this study we found that ES cell–derived DCs repre- 10 ES-DCs as stimulators were cocultured with 10 responders in wells of sented less mature cells compared with adult stem cell–derived 96-well round-bottom culture plates for 5 d. BrdU was added during the last 12 h of the culture. At the end of the culture, half of the cells were DCs. Furthermore, our gene expression analysis revealed that three centrifuged onto a 96-well plate, and the incorporation of BrdU was DC-affiliated transcription factors (IRF4, SPI-B, and RUNX3) were measured with a BrdU Cell Proliferation Assay Kit (Merck Millipore), poorly expressed in ES cell–derived DCs (ES-DCs). Remarkably, according to the manufacturer’s recommendations. improved DC maturation with enhanced chemotactic activity was Quantitative real-time RT-PCR detected on Runx3-instructed ES-DCs, suggesting
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