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Functional heterogeneity of IFN-γ-licensed mesenchymal stromal cell immunosuppressive capacity on biomaterials.

Proceedings of the National Academy of Sciences of the United States of America (2021-08-28)
Brian J Kwee, Johnny Lam, Adovi Akue, Mark A KuKuruga, Kunyu Zhang, Luo Gu, Kyung E Sung
RÉSUMÉ

Mesenchymal stromal cells (MSCs) are increasingly combined with biomaterials to enhance their therapeutic properties, including their immunosuppressive function. However, clinical trials utilizing MSCs with or without biomaterials have shown limited success, potentially due to their functional heterogeneity across different donors and among different subpopulations of cells. Here, we evaluated the immunosuppressive capacity, as measured by the ability to reduce T-cell proliferation and activation, of interferon-gamma (IFN-γ)-licensed MSCs from multiple donors on fibrin and collagen hydrogels, the two most commonly utilized biomaterials in combination with MSCs in clinical trials worldwide according to ClinicalTrials.gov Variations in the immunosuppressive capacity between IFN-γ-licensed MSC donors on the biomaterials correlated with the magnitude of indoleamine-2,3-dioxygenase activity. Immunosuppressive capacity of the IFN-γ-licensed MSCs depended on the αV/α5 integrins when cultured on fibrin and on the α2/β1 integrins when cultured on collagen. While all tested MSCs were nearly 100% positive for these integrins, sorted MSCs that expressed higher levels of αV/α5 integrins demonstrated greater immunosuppressive capacity with IFN-γ licensing than MSCs that expressed lower levels of these integrins on fibrin. These findings were equivalent for MSCs sorted based on the α2/β1 integrins on collagen. These results demonstrate the importance of integrin engagement to IFN-γ licensed MSC immunosuppressive capacity and that IFN-γ-licensed MSC subpopulations of varying immunosuppressive capacity can be identified by the magnitude of integrin expression specific to each biomaterial.

MATÉRIAUX
Référence du produit
Marque
Description du produit

Sigma-Aldrich
Fibrinogène from bovine plasma, Type I-S, 65-85% protein (≥75% of protein is clottable)
Sigma-Aldrich
Thrombine from bovine plasma, lyophilized powder, 40-300 NIH units/mg protein (biuret)
Sigma-Aldrich
Anticorps anti-intégrine alpha 5 (CD49e), clone mAb16, clone mAb16, from rat
Sigma-Aldrich
Rat IgG2a Negative Control, clone 2A3, Azide Free Antibody, clone 2A3, from rat, purified by affinity chromatography