Format

Send to

Choose Destination
Cell Death Dis. 2019 Jan 28;10(2):85. doi: 10.1038/s41419-019-1336-4.

IFNβ enhances mesenchymal stromal (Stem) cells immunomodulatory function through STAT1-3 activation and mTOR-associated promotion of glucose metabolism.

Author information

1
IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
2
Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples, Italy.
3
IRCSS Fondazione Santa Lucia, Rome, Italy.
4
Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, Bari, Italy.
5
Centre for Experimental Neurological Therapies (CENTERS), Sapienza University, Rome, Italy.
6
IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli, Italy.
7
Laboratory of Synaptic Immunopathology, Tor Vergata University, Rome, Italy.
8
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.
9
IRCCS Ospedale Policlinico San Martino, Genoa, Italy. auccelli@neurologia.unige.it.
10
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health Unit and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy. auccelli@neurologia.unige.it.

Abstract

Administration of mesenchymal stem cells (MSC) ameliorate experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), at both clinical and neuropathological levels. The therapeutic properties of MSC in EAE are mainly mediated by the modulation of pathogenic immune response, but other neurotropic effects, including decreased demyelination and axonal loss as well as promotion of tissue repair, play also a role. Properly controlled phase II clinical trials to explore the potential of MSC transplantation as a treatment for MS are underway. Interferon beta (IFNβ) is an approved treatment for relapsing-remitting and secondary progressive MS. Here, we explored the possibility that IFNβ might influence the therapeutic potential of MSC, in view of possible synergistic effects as add-on therapy. IFNβ enhanced the immunomodulatory functions of MSC and induced the expression of secretory leukocyte protease inhibitor (Slpi) and hepatocyte growth factor (Hgf), two soluble mediators involved in immune and regenerative functions of MSC. At molecular level, IFNβ induced a rapid and transient phosphorylation of STAT1 and STAT3, the transcription factors responsible for Slpi and Hgf induction. Concomitantly, IFNβ dynamically affected the activity of mTOR, a key checkpoint in the control of metabolic pathways. Indeed, the impairment of mTOR activity observed early upon exposure to IFNβ, was followed by a long-lasting induction of mTOR signaling, that was associated with an increased glycolytic capacity in MSC. When induced to switch their energetic metabolism towards glycolysis, MSC showed an improved ability to control T-cell proliferation. These results suggest that modifications of MSC energetic metabolism induced by IFNβ may contribute to promote MSC immunomodulatory function and support a role for metabolic pathways in the therapeutic function of MSC. Altogether, these findings support the idea of a combined treatment for MS, in which the immunomodulatory and possibly regenerative activity of MSC could be enhanced by the administration of IFNβ.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center