TGF-ß1-Licensed Murine MSCs show superior therapeutic efficacy in modulating corneal allograft immune rejection In Vivo
Lynch, Kevin Treacy, Oliver Chen, Xizhe Murphy, Nick Lohan, Paul Islam, Md Nahidul Donohoe, Ellen Griffin, Matthew D. Watson, Luke McLoughlin, Steven
Lynch, Kevin
Treacy, Oliver
Chen, Xizhe
Murphy, Nick
Lohan, Paul
Islam, Md Nahidul
Donohoe, Ellen
Griffin, Matthew D.
Watson, Luke
McLoughlin, Steven
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Publication Date
2020-05-29
Type
Article
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Citation
Lynch, 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.2020.05.023
Abstract
Mesenchymal 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.
Publisher
Elsevier
Publisher DOI
10.1016/j.ymthe.2020.05.023
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Attribution-NonCommercial-NoDerivs 3.0 Ireland