title: PI3kα and STAT1 Interplay Regulates Human Mesenchymal Stem Cell Immune Polarization.
abstract: The immunomodulatory capacity of mesenchymal stem cells (MSCs) is critical for their use in therapeutic applications. MSC response to specific inflammatory cues allows them to switch between a proinflammatory (MSC1) or anti-inflammatory (MSC2) phenotype. Regulatory mechanisms controlling this switch remain to be defined. One characteristic feature of MSC2 is their ability to respond to IFNγ with induction of indoleamine 2,3-dioxygenase (IDO), representing the key immunoregulatory molecule released by human MSC. Here, we show that STAT1 and PI3Kα pathways interplay regulates IFNγ-induced IDO production in MSC. Chemical phosphoinositide 3-kinase (PI3K) pan-inhibition, PI3Kα-specific inhibition or shRNA knockdown diminished IFNγ-induced IDO production. This effect involved PI3Kα-mediated upregulation of STAT1 protein levels and phosphorylation at Ser727. Overexpression of STAT1 or of a constitutively active PI3Kα mutant failed to induce basal IDO production, but shifted MSC into an MSC2-like phenotype by strongly enhancing IDO production in response to IFNγ as compared to controls. STAT1 overexpression strongly enhanced MSC-mediated T-cell suppression. The same effect could be induced using short-term pretreatment of MSC with a chemical inhibitor of the counter player of PI3K, phosphatase and tensin homolog. Finally, downregulation of STAT1 abrogated the immunosuppressive capacity of MSC. Our results for the first time identify critical upstream signals for the induced production of IDO in MSCs that could be manipulated therapeutically to enhance their immunosuppressive phenotype.
authors.affiliation: Transplantation Research Center, Brigham and Women's and Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Marwan
authors.initials: M
authors.lastname: Mounayar
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Eirini
authors.initials: E
authors.lastname: Kefaloyianni
authors.affiliation: Transplantation Research Center, Brigham and Women's and Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Smith
authors.affiliation: Transplantation Research Center, Brigham and Women's and Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Zhabiz
authors.initials: Z
authors.lastname: Solhjou
authors.affiliation: Transplantation Research Center, Brigham and Women's and Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Omar H
authors.initials: OH
authors.lastname: Maarouf
authors.affiliation: Transplantation Research Center, Brigham and Women's and Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Jamil
authors.initials: J
authors.lastname: Azzi
authors.affiliation: Transplantation Research Center, Brigham and Women's and Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Lola
authors.initials: L
authors.lastname: Chabtini
authors.affiliation: Transplantation Research Center, Brigham and Women's and Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
authors.affiliation: Viacord LLC, A PerkinElmer Company, Cambridge, Massachusetts, USA.
authors.forename: Morey
authors.initials: M
authors.lastname: Kraus
authors.affiliation: ViaCord Processing Lab, ViaCord LLC, A PerkinElmer Company, Hebron, Kentucky, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Briddell
authors.affiliation: The Cell Therapy Group, Madison, Connecticut, USA.
authors.forename: William
authors.initials: W
authors.lastname: Fodor
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrlich
authors.affiliation: Transplantation Research Center, Brigham and Women's and Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Reza
authors.initials: R
authors.lastname: Abdi
mesh_terms: D002454:Cell Differentiation; D058534:Class I Phosphatidylinositol 3-Kinases; D015536:Down-Regulation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
keywords: Cell signaling; Immunosuppression; Immunotherapy; Interferon gamma; Mesenchymal stem cells; PI3K alpha; STAT1; T cells