Pluto Bioinformatics

GSE150008: TGF-1 licensed murine mesenchymal stromal cells show superior therapeutic efficacy in modulating corneal allograft immune rejection in vivo

Bulk RNA sequencing

We report a novel licensing strategy to improve the immunosuppressive capacity of MSCs. Licensing murine MSCs with TGF-1 (TGF- MSC) 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 (Tregs) following co-culture assays. These TGF- MSC-expanded Tregs 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- MSCs could significantly prolong rejection-free survival (69.2% acceptance rate compared to 21.4% for un-licensed MSC treated recipients) in a murine corneal allograft model.; Mechanistic studies revealed that (i) therapeutic efficacy of TGF- MSCs is Smad2/3-dependent; (ii) TGF- MSCs enhanced immunosuppressive capacity is contact-dependent and (iii) enhanced secretion of PGE2 (via prostaglandin EP4 receptor) by TGF- 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-1 licensing as an unconventional strategy for enhancing MSC immunosuppressive capacity. SOURCE: Aideen Ryan National University of Ireland, Galway

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