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dc.contributor.authorLynch, Kevin
dc.contributor.authorTreacy, Oliver
dc.contributor.authorChen, Xizhe
dc.contributor.authorMurphy, Nick
dc.contributor.authorLohan, Paul
dc.contributor.authorIslam, Md Nahidul
dc.contributor.authorDonohoe, Ellen
dc.contributor.authorGriffin, Matthew D.
dc.contributor.authorWatson, Luke
dc.contributor.authorMcLoughlin, Steven
dc.contributor.authorO'Malley, Grace
dc.contributor.authorRyan, Aideen E.
dc.contributor.authorRitter, Thomas
dc.date.accessioned2020-07-13T13:46:55Z
dc.date.available2020-07-13T13:46:55Z
dc.date.issued2020-05-29
dc.identifier.citationLynch, Kevin, Treacy, Oliver, Chen, Xizhe, Murphy, Nick, Lohan, Paul, Islam, Md Nahidul, Donohoe, Ellen Griffin, Matthew D., Watson, Luke, McLoughlin, Steven, O’Malley, Grace, Ryan, Aideen E., Ritter, Thomas. (2020). TGF-β1-Licensed Murine MSCs Show Superior Therapeutic Efficacy in Modulating Corneal Allograft Immune Rejection In Vivo. Molecular Therapy. doi:https://doi.org/10.1016/j.ymthe.2020.05.023en_IE
dc.identifier.issn1525-0024
dc.identifier.urihttp://hdl.handle.net/10379/16073
dc.description.abstractMesenchymal stromal cells (MSCs) are a promising therapeutic option for multiple immune diseases/disorders; however, efficacy of MSC treatments can vary significantly. We present a novel licensing strategy to improve the immunosuppressive capacity of MSCs. Licensing murine MSCs with transforming growth factor-ß1 (TGF-ß MSCs) significantly improved their ability to modulate both the phenotype and secretome of inflammatory bone marrow-derived macrophages and significantly increased the numbers of regulatory T lymphocytes following co-culture assays. These TGF-ß MSC-expanded regulatory T lymphocytes also expressed significantly higher levels of PD-L1 and CD73, indicating enhanced suppressive potential. Detailed analysis of T lymphocyte co-cultures revealed modulation of secreted factors, most notably elevated prostaglandin E2 (PGE2). Furthermore, TGF-ß MSCs could significantly prolong rejection-free survival (69.2% acceptance rate compared to 21.4% for unlicensed MSC-treated recipients) in a murine corneal allograft model. Mechanistic studies revealed that (1) therapeutic efficacy of TGF-ß MSCs is Smad2/3-dependent, (2) the enhanced immunosuppressive capacity of TGF-ß MSCs is contact-dependent, and (3) enhanced secretion of PGE2 (via prostaglandin EP4 [E-type prostanoid 4] receptor) by TGF-ß MSCs is the predominant mediator of Treg expansion and T cell activation and is associated with corneal allograft survival. Collectively, we provide compelling evidence for the use of TGF-ß1 licensing as an unconventional strategy for enhancing MSC immunosuppressive capacity.en_IE
dc.description.sponsorshipThis study was supported by a Science Foundation Ireland Investigator Award (grant 12/IA/1624; to T.R.). This work was also supported by grants from the Health Research Board of Ireland (grant HRA_POR/2013/341 to M.D.G. and T.R.); a Science Foundation Ireland Starting Investigator grant (15/SIRG/3456 to A.E.R.); the European Union European Commission under the Seventh Framework (EU FP7) Collaborative Health Project VISICORT (Adverse Immune Responses and Their Prevention in Corneal Transplantation) (grant 602470 to M.D.G. and T.R.); and the European Regional Development Fund.en_IE
dc.formatapplication/pdfen_IE
dc.language.isoenen_IE
dc.publisherElsevieren_IE
dc.relation.ispartofMolecular Therapy : The Journal Of The American Society Of Gene Therapyen
dc.subjectmesenchymal stromal cellsen_IE
dc.subjectcytokine licensingen_IE
dc.subjectTGF-β1en_IE
dc.subjectcorneal transplantationen_IE
dc.subjectimmunosuppressionen_IE
dc.subjectautologousen_IE
dc.subjectMSC therapyen_IE
dc.subjectTregen_IE
dc.subjectimmunomodulationen_IE
dc.subjectPGE2en_IE
dc.subjectRNA sequencingen_IE
dc.titleTGF-ß1-Licensed Murine MSCs show superior therapeutic efficacy in modulating corneal allograft immune rejection In Vivoen_IE
dc.typeArticleen_IE
dc.date.updated2020-07-12T09:49:57Z
dc.identifier.doi10.1016/j.ymthe.2020.05.023
dc.local.publishedsourcehttps://doi.org/10.1016/j.ymthe.2020.05.023en_IE
dc.description.peer-reviewedpeer-reviewed
dc.contributor.funderScience Foundation Irelanden_IE
dc.contributor.funderHealth Research Boarden_IE
dc.contributor.funderSeventh Framework Programmeen_IE
dc.contributor.funderEuropean Regional Development Funden_IE
dc.internal.rssid21810777
dc.local.contactThomas Ritter, School Of Medicine, Regenerative Medicine Institute, Biosciences, Dangan. 5329 Email: thomas.ritter@nuigalway.ie
dc.local.copyrightcheckedYes we have paid for open access
dc.local.versionPUBLISHED
dcterms.projectinfo:eu-repo/grantAgreement/SFI/SFI Investigator Programme/12/IA/1624/IE/Novel therapeutic approaches to improve corneal allograft survival by cell and gene therapy and insights into the mechanism of action/en_IE
dcterms.projectinfo:eu-repo/grantAgreement/SFI/SFI Starting Investigator Research Grant (SIRG)/15/SIRG/3456/IE/'RESTRAIN' Investigation of tumour stromal interactions in metastatic colon cancer for the identification of novel immuno-therapeutic targets/en_IE
dcterms.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::HEALTH/602470/EU/Adverse Immune Signatures and their Prevention in Corneal Transplantation/VISICORTen_IE
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