Date: Saturday, May 2, 2015
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Exhibit Hall E
The immunomodulatory capacity of mesenchymal stem cells (MSC) is critical for their use in therapeutic applications. MSC response to specific inflammatory cues allows them to switch between a pro-inflammatory (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 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. Finally, downregulation of STAT1 abrogated the immunosuppressive capacity of MSC in a T-cell suppression assay, while STAT1 overexpression significantly enhanced it. 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 the immunosuppressive MSC2 phenotype.
To cite this abstract in AMA style:Kefalogianni E, Mounayar M, Smith B, Azzi J, Chabtini L, Fiorina P, Kraus M, Briddell R, Fodor W, Herrlich A, Abdi R. PI3Kα and STAT1 Interplay Regulates Human Mesenchymal Stem Cell Immune Polarization [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/pi3k-and-stat1-interplay-regulates-human-mesenchymal-stem-cell-immune-polarization/. Accessed June 12, 2021.
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