Abstract
Bone marrow mesenchymal stem cells (MSCs) comprise a heterogeneous population of postnatal progenitor cells with profound immunomodulatory properties, such as upregulation of Foxp3+ regulatory T cells (Tregs) and downregulation of Th17 cells. However, it is unknown whether different MSC subpopulations possess the same range of immunomodulatory function. Here, we show that a subset of single colony-derived MSCs producing IL-17 is different from bulk MSC population in that it cannot upregulate Tregs, downregulate Th17 cells, or ameliorate disease phenotypes in a colitis mouse model. Mechanistically, we reveal that IL-17, produced by these MSCs, activates the NFκB pathway to downregulate TGF-β production in MSCs, resulting in abolishment of MSC-based immunomodulation. Furthermore, we show that NFκB is able to directly bind to TGF-β promoter region to regulate TGF-β expression in MSCs. Moreover, these IL-17+ MSCs possess anti-Candida albicans growth effects in vitro and therapeutic effect in C. albicans-infected mice. In summary, this study shows that MSCs contain an IL-17+ subset capable of inhibiting C. albicans growth, but attenuating MSC-based immunosuppression via NFκB-mediated downregulation of TGF-β.
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Acknowledgements
This work was supported by grants from the National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Department of Health and Human Services (R01DE017449, R01 DE019932, and R01 DE019413 to S S), the Ministry of Science and Technology of China (2010DFB32980 to Y Z), and the Intramural Research Program of NIDCR, NIH (to W J C).
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
Supplementary information
Supplementary information, Figure S1
Flow cytometric analysis showed that hMSCs and mMSCs expressed stem cell markers CD146 and Sca1, but not hematopoietic markers CD34, CD3, CD4 and CD8a. (PDF 1166 kb)
Supplementary information, Figure S2
Immunofluorescent and immunocytochemical staining showed that hMSCs were positive for stem cell markers CD146 and Sca1, but negative for T cell markers CD3, CD4 and CD8a. (PDF 9091 kb)
Supplementary information, Figure S3
Flow cytometric analysis showed the efficacy of CD3 antibody/complement–mediated depletion of CD3+ T cells in hPBMCs. (PDF 239 kb)
Supplementary information, Figure S4
IL-17 expression was regulated by IL-1β and IL-6 via activating Stat3 and RORγt. (PDF 642 kb)
Supplementary information, Figure S5
Flow cytometric analysis showed that IL-17+ MSCs (#2, #3, and #4) expressed stem cell markers CD146 and Sca1, but not hematopoietic markers CD34, CD3, CD4 and CD8a. (PDF 2111 kb)
Supplementary information, Figure S6
Single colony-derived hMSCs possess stem cell properties. (PDF 471 kb)
Supplementary information, Figure S7
Western blot analysis showed efficacy of IL-17, IL-17R, and IκB kinase α siRNA in hMSCs. (PDF 930 kb)
Supplementary information, Figure S8
(A) Western blot analysis showed that recombinant IL-17 treatment increased p-IκBα and p-p65 in MSCs. (PDF 214 kb)
Supplementary information, Figure S9
Schematic diagram shows the mechanism by which IL-17+ MSCs attenuate immunosuppressive capacities, but possess increased anti-C. albicans activity. (PDF 205 kb)
Supplementary information, Table S1
PCR primers (PDF 98 kb)
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Yang, R., Liu, Y., Kelk, P. et al. A subset of IL-17+ mesenchymal stem cells possesses anti-Candida albicans effect. Cell Res 23, 107–121 (2013). https://doi.org/10.1038/cr.2012.179
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DOI: https://doi.org/10.1038/cr.2012.179
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