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.

Hepatitis C Virus Induces MDSCs-Like Monocytes through TLR2/PI3K/AKT/STAT3 Signaling

“…We further found that HCVc-induced IDO1 expression and IL-10 production were inhibited by either PI3K or STAT3 inhibitors, and the inhibitors of PI3K and STAT3 also reversed the inhibition of HLA-DR expression by HCVc and HCVcc (Fig 6). A previous study has reported that PI3K-specific inhibition or shRNA knockdown diminishes IFNγ-induced IDO production [44]. These results suggest that HCV employs HCVc to induce MDSC-like suppressive monocytes through the TLR2/PI3K/AKT/STAT3 signaling pathway.…”

Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing

“…In order to tightly control the microenvironment of LN, FRCs carry the potential to have both proinflammatory and regulatory functions (23,67). The initiation of immunoregulatory processes mediated by FRCs within the KLN likely promotes organ healing by suppressing inflammatory responses (68)(69)(70)(71).…”

Macrophage interactions with polylactic acid and chitosan scaffolds lead to improved recruitment of human mesenchymal stem/stromal cells: a comprehensive study with different immune cells

“…RANTES can impact on MSC chemotaxis and also on other key functions linked with their regenerative potential. Indeed, it was recently shown that the immunosuppressive ability of MSC relies on STAT-1 signalling [35], which in these cells can be specifically activated by RANTES [36,37]. Therefore, interactions of monocytes and NK cells with biomaterials hamper expression of key chemokines and, as a consequence, MSC recruitment.…”