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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.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:
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.relation.ispartofMolecular Therapy : The Journal Of The American Society Of Gene Therapyen
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 Ireland
dc.subjectmesenchymal stromal cellsen_IE
dc.subjectcytokine licensingen_IE
dc.subjectcorneal transplantationen_IE
dc.subjectMSC therapyen_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.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.local.contactThomas Ritter, School Of Medicine, Regenerative Medicine Institute, Biosciences, Dangan. 5329 Email:
dc.local.copyrightcheckedYes we have paid for open access
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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