IFN-γ orchestrates mesenchymal stem cell plasticity through the signal transducer and activator of transcription 1 and 3 and mammalian target of rapamycin.

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Presentation transcript:

IFN-γ orchestrates mesenchymal stem cell plasticity through the signal transducer and activator of transcription 1 and 3 and mammalian target of rapamycin pathways Tiziana Vigo, PhD, Claudio Procaccini, PhD, Giovanni Ferrara, PhD, Sergio Baranzini, PhD, Jorge R. Oksenberg, PhD, Giuseppe Matarese, MD, PhD, Alberto Diaspro, BS, Nicole Kerlero de Rosbo, PhD, Antonio Uccelli, MD Journal of Allergy and Clinical Immunology Volume 139, Issue 5, Pages 1667-1676 (May 2017) DOI: 10.1016/j.jaci.2016.09.004 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2017 139, 1667-1676DOI: (10 Journal of Allergy and Clinical Immunology 2017 139, 1667-1676DOI: (10.1016/j.jaci.2016.09.004) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 IFN-γ–induced STAT1 and STAT3 activation promotes mMSC immunomodulation. A-C, Representative Western blot of mMSCs exposed to IFN-γ (10 ng/mL; Fig 1, A) and relative densitometric quantification after 1 hour (Fig 1, B) and 24 hours (Fig 1, C), respectively. D, Representative in vitro T-cell proliferation assay plot. E, Proliferating T cells in the presence or absence of CTRL-KD, STAT1-KD and STAT3-KD mMSCs. F-G, PCR analysis of the expression of Cd274, Nos2, and Il18bp in CTRL-KD, STAT1-KD and STAT3-KD mMSCs. Journal of Allergy and Clinical Immunology 2017 139, 1667-1676DOI: (10.1016/j.jaci.2016.09.004) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 mTOR inhibition promotes mMSC immunoregulatory function. A, PCR analysis of the expression of Cd274, Nos2, and Il18bp in mMSCs exposed or not to RAPA. B, In vitro T-cell proliferation assay in the presence of MSCs and RAPA MSCs or CTRL-KD and RHEB-KD MSCs. C, proliferating T cells in the presence or absence of MSCs and RAPA, CTRL-KD, and RHEB-KD MSCs. Journal of Allergy and Clinical Immunology 2017 139, 1667-1676DOI: (10.1016/j.jaci.2016.09.004) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Inhibition of mTOR improves the ability of MSCs to control DTH. The DTH response to OVA323-339 in mice intravenously injected or not with MSCs or RAPA MSCs (A) or with CTRL-KD or RHEB-KD MSCs (B) is shown. Journal of Allergy and Clinical Immunology 2017 139, 1667-1676DOI: (10.1016/j.jaci.2016.09.004) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 ERK1/2-dependent mTOR inhibition promotes nuclear translocation of pSTAT1. A and G, Confocal analysis of pSTAT1 (red) localization in mMSCs, RAPA MSCs (Fig 4, A), and U0126 mMSCs (Fig 4, G). B and H, Quantification of the colocalization between the 2 fluorophores 4′-6-diamidino-2-phenylindole dihydrochloride (blue) and Alexa Fluor 594 (red) by using the Pearson index. C and D, Representative Western blot of mMSCs and U0126 mMSCs primed or not with IFN-γ (Fig 4, C) and its densitometric quantification after normalization of phosphorylated protein on its total form (Fig 4, D). E, Western blot analysis conducted after 1 or 24 hours of incubation with IFN-γ. F, Relative densitometric quantitation of pERK1/2 after normalization of phosphorylated protein on its total form. Journal of Allergy and Clinical Immunology 2017 139, 1667-1676DOI: (10.1016/j.jaci.2016.09.004) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 IFN-γ–induced changes of STAT3 and mTOR pathways in human MSCs affect inhibition of T-cell proliferation. A-C, Western blotting of hMSCs exposed to IFN-γ (10 ng/mL; Fig 5, A) and its relative densitometric quantification after 1 hour (Fig 5, B) and 24 hours (Fig 5, C). D, In vitro T-cell proliferation assay in the presence of hMSCs and CUC hMSCs. E, Proliferating T cells in the presence of MSC and CUC MSCs. F, PCR analysis of the expression of Cd274 and Il18bp in hMSCs and RAPA hMSCs. G, In vitro T-cell proliferation assay in the presence of hMSCs and RAPA hMSCs. H, Proliferating T cells in the presence or absence of hMSCs and RAPA hMSCs. Journal of Allergy and Clinical Immunology 2017 139, 1667-1676DOI: (10.1016/j.jaci.2016.09.004) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2017 139, 1667-1676DOI: (10.1016/j.jaci.2016.09.004) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2017 139, 1667-1676DOI: (10.1016/j.jaci.2016.09.004) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2017 139, 1667-1676DOI: (10.1016/j.jaci.2016.09.004) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2017 139, 1667-1676DOI: (10.1016/j.jaci.2016.09.004) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2017 139, 1667-1676DOI: (10.1016/j.jaci.2016.09.004) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions