Format

Send to

Choose Destination
J Allergy Clin Immunol. 2017 May;139(5):1667-1676. doi: 10.1016/j.jaci.2016.09.004. Epub 2016 Sep 23.

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

Author information

1
Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-infantili, Facoltà di Medicina e Chirurgia, Università di Genova, Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), Genoa, Italy.
2
Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR) c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," Naples, Italy.
3
Department of Neurology, University of California, San Francisco, Calif.
4
Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR) c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," Naples, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," Naples, Italy.
5
Nanophysics, Istituto Italiano di Tecnologia, Genoa, Italy.
6
Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-infantili, Facoltà di Medicina e Chirurgia, Università di Genova, Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), Genoa, Italy; IRCCS AOU San Martino-IST, Genoa, Italy. Electronic address: auccelli@neurologia.unige.it.

Abstract

BACKGROUND:

Mesenchymal stem cells (MSCs) display a therapeutic plasticity because of their ability to modulate immunity, foster tissue repair, and differentiate into mesodermal cells. IFN-γ has been described to differently affect human mesenchymal stem cell (hMSC) and mouse mesenchymal stem cell (mMSC) immunomodulation and differentiation, depending on the inflammatory milieu.

OBJECTIVE:

We aimed at dissecting the relevant intracellular pathways through which IFN-γ affects MSC plasticity and the consequence of their manipulation on MSC functions.

METHODS:

Modification of relevant IFN-γ-dependent pathways in mMSCs was carried out in vitro through gene silencing or chemical inhibition of key components. Functional outcomes were assessed by means of Western blotting, real-time PCR, differentiation, and proliferation assays on MSCs. The effect on T cells was addressed by T-cell proliferation assays; the effect of mammalian target of rapamycin (mTOR) manipulation in MSCs was studied in vivo in a mouse model of delayed-type hypersensitivity assay. To address whether similar mechanisms are involved also in hMSCs on IFN-γ stimulation, the effect of chemical inhibition on the same intracellular pathways was assessed by means of Western blotting, and the final outcome on immunomodulatory properties was evaluated based on real-time PCR and T-cell proliferation.

RESULTS:

We revealed that in mMSCs IFN-γ-induced immunoregulation is mediated by early phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT3, which is significantly enhanced by an extracellular signal-regulated kinase 1/2-dependent mTOR inhibition, thereby promoting pSTAT1 nuclear translocation. Accordingly, after intracellular mTOR inhibition, MSCs augmented their ability to inhibit T-cell proliferation and control delayed-type hypersensitivity in vivo. Similarly, on mTOR blockade, hMSCs also enhanced their immunoregulatory features. A sustained exposure to IFN-γ led to inhibition of STAT3 activity, which in mMSCs resulted in an impaired proliferation and differentiation.

CONCLUSION:

These results provide new insights about MSC intracellular pathways affected by IFN-γ, demonstrating that pharmacologic or genetic manipulation of MSCs can enhance their immunomodulatory functions, which could be translated into novel therapeutic approaches.

KEYWORDS:

IFN-γ; T cells; immunomodulation; mammalian target of rapamycin; mesenchymal stem cells; signal transducer and activator of transcription 1; signal transducer and activator of transcription 3

PMID:
27670240
DOI:
10.1016/j.jaci.2016.09.004
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center