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Oxygen Tension And Indolamine 2,3-dioxygenase Expression Regulate Mesenchymal Stem Cell-mediated Regulatory T Cell Expansion
Rohini Kadle, BS, Johnathan Massie, BS, Trevor Ellison, BS, Sophia Hameedi, N/A, Piul Rabbani, PhD, Bukhtawar Waqas, BS, Daniel Ceradini, MD.
NYU, New York, NY, USA.

PURPOSE: Mesenchymal stem cells (MSCs) have powerful immunosuppressive properties, partially mediated by expansion of regulatory T cells populations (Tregs). We previously showed that priming MSCs with hypoxic and inflammatory conditions enhances their stem-like and immunomodulatory properties, largely through induction of indolamine 2,3-dioxygenase (IDO). We therefore hypothesize that priming MSCs will increase MSC-mediated Treg expansion via an IDO-specific mechanism.
METHODS: We harvested CD4+ T cells from Lewis rat spleens and co-cultured them with MSCs and allogeneic rat endothelial cells (ECs). MSCs were cultured in either hypoxia (5% O2) or normoxia, or primed with inflammatory cytokine IFNy. Flow cytometry for FoxP3 determined %Tregs.
RESULTS: With MSC/CD4+/EC co-culture, %Tregs tripled to 24.13±2.16%, versus CD4+/EC(9.28±1.15%) or CD4+ alone (7.94±1.22%), p<0.0001 for both. When MSCs were physically separated in culture from CD4+/ECs, %Tregs was similar to MSC/CD4+/EC (27.77±1.99% vs 22.6±5.65%). Using hypoxia-primed MSCs, %Tregs more than doubled to 24.13±2.16% vs 11.06±2.19% with normoxic MSCs (p<0.01). When we inhibited IDO, %Tregs significantly decreased to 12.4± 3.10% (p<0.01), almost negating effects of MSCs on Treg proliferation. Priming MSCs with IFNγ had no impact on % Tregs, in normoxia and hypoxia.
CONCLUSION: Addition of autologous MSCs to co-culture increases Treg proliferation, which is potentiated by hypoxia-primed MSCs. MSC-mediated Treg expansion does not require direct contact, indicating a paracrine mechanism. Inhibition of IDO significantly decreases the proliferation of Tregs, implying a key role of IDO. These results further delineate the mechanisms by which MSCs exert their immunomodulatory functions, demonstrating methods to prime MSCs to optimize their immunomodulation.


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