Dual IFN-γ/hypoxia priming enhances immunosuppression of mesenchymal stromal cells through regulatory proteins and metabolic mechanisms
The immunosuppressive capacity of human mesenchymal stromal cells (MSCs) renders them promising candidates for treating diverse immune disorders. However, after hundreds of clinical trials, there are still no MSC therapies approved in the United States. MSCs require specific cues to adopt their immu...
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Published in | Journal of immunology and regenerative medicine Vol. 1; pp. 45 - 56 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Netherlands
01.03.2018
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Subjects | |
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Abstract | The immunosuppressive capacity of human mesenchymal stromal cells (MSCs) renders them promising candidates for treating diverse immune disorders. However, after hundreds of clinical trials, there are still no MSC therapies approved in the United States. MSCs require specific cues to adopt their immunosuppressive phenotype, and yet most clinical trials use cells expanded in basic culture medium and growth conditions. We propose that priming MSCs prior to administration will improve their therapeutic efficacy. Interferon-gamma (IFN-γ) priming are cues common to situations of immune escape that have individually shown promise as MSC priming cues but have not been systematically compared. Using mixed lymphocyte reactions, we show that priming MSCs with either cue alone improves T-cell inhibition. However, combining the two cues results in additive effects and markedly enhances the immunosuppressive phenotype of MSCs. We demonstrate that IFN-γ induces expression of numerous immunosuppressive proteins (IDO, PD-L1, HLA-E, HLA-G), whereas hypoxia switches MSCs to glycolysis, causing rapid glucose consumption and production of T-cell inhibitory lactate levels. Dual IFN-γ/hypoxia primed MSCs display both attributes and have even higher induction of immunosuppressive proteins over IFN-γ priming alone (IDO and HLA-G), which may reflect another benefit of metabolic reconfiguration. |
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AbstractList | The immunosuppressive capacity of human mesenchymal stromal cells (MSCs) renders them promising candidates for treating diverse immune disorders. However, after hundreds of clinical trials, there are still no MSC therapies approved in the United States. MSCs require specific cues to adopt their immunosuppressive phenotype, and yet most clinical trials use cells expanded in basic culture medium and growth conditions. We propose that priming MSCs prior to administration will improve their therapeutic efficacy. Interferon-gamma (IFN-γ) priming are cues common to situations of immune escape that have individually shown promise as MSC priming cues but have not been systematically compared. Using mixed lymphocyte reactions, we show that priming MSCs with either cue alone improves T-cell inhibition. However, combining the two cues results in additive effects and markedly enhances the immunosuppressive phenotype of MSCs. We demonstrate that IFN-γ induces expression of numerous immunosuppressive proteins (IDO, PD-L1, HLA-E, HLA-G), whereas hypoxia switches MSCs to glycolysis, causing rapid glucose consumption and production of T-cell inhibitory lactate levels. Dual IFN-γ/hypoxia primed MSCs display both attributes and have even higher induction of immunosuppressive proteins over IFN-γ priming alone (IDO and HLA-G), which may reflect another benefit of metabolic reconfiguration.
The MSC single (IFN-γ or hypoxia) and dual (IFN-γ + hypoxia)
in
vitro priming regimens were evaluated for their capacity to promote strong and homogenous immunosuppressive phenotype. The immunosuppressive capacity of human mesenchymal stromal cells (MSCs) renders them promising candidates for treating diverse immune disorders. However, after hundreds of clinical trials, there are still no MSC therapies approved in the United States. MSCs require specific cues to adopt their immunosuppressive phenotype, and yet most clinical trials use cells expanded in basic culture medium and growth conditions. We propose that priming MSCs prior to administration will improve their therapeutic efficacy. Interferon-gamma (IFN-γ) priming are cues common to situations of immune escape that have individually shown promise as MSC priming cues but have not been systematically compared. Using mixed lymphocyte reactions, we show that priming MSCs with either cue alone improves T-cell inhibition. However, combining the two cues results in additive effects and markedly enhances the immunosuppressive phenotype of MSCs. We demonstrate that IFN-γ induces expression of numerous immunosuppressive proteins (IDO, PD-L1, HLA-E, HLA-G), whereas hypoxia switches MSCs to glycolysis, causing rapid glucose consumption and production of T-cell inhibitory lactate levels. Dual IFN-γ/hypoxia primed MSCs display both attributes and have even higher induction of immunosuppressive proteins over IFN-γ priming alone (IDO and HLA-G), which may reflect another benefit of metabolic reconfiguration. |
Author | Wobma, Holly M Shih, Ying Duran-Struuck, Raimon Ma, Stephen P Kanai, Mariko Goeta, Shahar Winchester, Robert Brown, Lewis M Li, Hao Wei Vunjak-Novakovic, Gordana |
AuthorAffiliation | a Department of Biomedical Engineering, Columbia University, New York, NY, USA b Columbia Center for Translational Immunology, Columbia University, New York, NY, USA f Quantitative Proteomics and Metabolomics Center, Columbia University, New York, NY, USA d Department of Pathology, Columbia University, New York, NY, USA c Department of Pathobiology, University of Pennsylvania, Philadelphia, PA, USA e Department of Medicine, Columbia University, New York, NY, USA |
AuthorAffiliation_xml | – name: f Quantitative Proteomics and Metabolomics Center, Columbia University, New York, NY, USA – name: b Columbia Center for Translational Immunology, Columbia University, New York, NY, USA – name: e Department of Medicine, Columbia University, New York, NY, USA – name: c Department of Pathobiology, University of Pennsylvania, Philadelphia, PA, USA – name: d Department of Pathology, Columbia University, New York, NY, USA – name: a Department of Biomedical Engineering, Columbia University, New York, NY, USA |
Author_xml | – sequence: 1 givenname: Holly M surname: Wobma fullname: Wobma, Holly M organization: Department of Biomedical Engineering, Columbia University, New York, NY, USA – sequence: 2 givenname: Mariko surname: Kanai fullname: Kanai, Mariko organization: Department of Biomedical Engineering, Columbia University, New York, NY, USA – sequence: 3 givenname: Stephen P surname: Ma fullname: Ma, Stephen P organization: Department of Biomedical Engineering, Columbia University, New York, NY, USA – sequence: 4 givenname: Ying surname: Shih fullname: Shih, Ying organization: Department of Biomedical Engineering, Columbia University, New York, NY, USA – sequence: 5 givenname: Hao Wei surname: Li fullname: Li, Hao Wei organization: Columbia Center for Translational Immunology, Columbia University, New York, NY, USA – sequence: 6 givenname: Raimon surname: Duran-Struuck fullname: Duran-Struuck, Raimon organization: Department of Pathobiology, University of Pennsylvania, Philadelphia, PA, USA – sequence: 7 givenname: Robert surname: Winchester fullname: Winchester, Robert organization: Department of Medicine, Columbia University, New York, NY, USA – sequence: 8 givenname: Shahar surname: Goeta fullname: Goeta, Shahar organization: Quantitative Proteomics and Metabolomics Center, Columbia University, New York, NY, USA – sequence: 9 givenname: Lewis M surname: Brown fullname: Brown, Lewis M organization: Quantitative Proteomics and Metabolomics Center, Columbia University, New York, NY, USA – sequence: 10 givenname: Gordana surname: Vunjak-Novakovic fullname: Vunjak-Novakovic, Gordana organization: Department of Medicine, Columbia University, New York, NY, USA |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30364570$$D View this record in MEDLINE/PubMed |
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