B7‑H1‑mediated immunosuppressive properties in human mesenchymal stem cells are mediated by STAT‑1 and not PI3K/Akt signaling

Abstract

Mesenchymal stem cells (MSCs), derived from either bone marrow (BM) or Wharton's jelly (WJ), inhibit the proliferation of activated T cells, and interferon (IFN)‑γ serves an important role in this process. This process is B7‑homolog (H)1‑dependent during cell contact inhibition. However, the signaling pathway involved in B7‑H1 expression in MSCs remains largely undefined. The present study demonstrated activation of B7‑H1 by engaging signal transducer and activator of transcription (STAT)‑1 signaling in MSCs. Human BM‑ and WJ‑MSCs were isolated and cultured. The immunosuppressive effect of BM‑ and WJ‑MSCs on phytohemagglutinin (PHA)‑induced T cell proliferation was compared using direct and indirect co‑culture systems. B7‑H1 expression on BM‑ and WJ‑MSCs was detected by flow cytometry. Small interfering (si)RNA was used to knock down the expression of STAT‑1. The inhibitory effect of MSCs on T lymphocytes was observed using PHA‑induced T cell proliferation assays. IFN‑γ‑induced B7‑H1 expression on human BM‑ and WJ‑MSCs increased in a time‑dependent manner. Furthermore, the inhibitory effect of MSCs on T cell proliferation was be restored when an anti‑B7‑H1 monoclonal antibody was used. When STAT‑1 signaling was inhibited by siRNA, B7‑H1 expression on IFN‑γ‑treated MSCs decreased and T cell proliferation was restored; however, the expression of B7‑H1 did not alter upon treatment with a phosphatidylinositol‑3‑kinase (PI3K) inhibitor (LY294002). These results demonstrated that the IFN‑γ‑induced immunosuppressive properties of B7‑H1 in human BM‑ and WJ‑MSCs were mediated by STAT‑1 signaling, and not by PI3K/RAC‑α serine/threonine‑protein kinase signaling. Understanding the intracellular mechanisms underlying IFN‑γ‑induced expression of B7‑H1 in MSCs may ultimately lead to an improved understanding of MSCs and provide insight into their use as cell therapy agents.

B7-H1 Promotes the Functional Effect of Human Gingiva-Derived Mesenchymal Stem Cells on Collagen-Induced Arthritis Murine Model

“…34,[46][47][48][49] B7-H1 also has been shown to have considerable importance for the immunosuppressive properties of BMSCs and WJMSCs. 50 Here, we identified that B7-H1 transcriptional and translational properties were expressed to a higher degree on GMSCs compared with control cells, and especially higher on a specific GMSC cluster. Moreover, after separating GMSCs into B7-H1 high and B7-H1 low expressed subsets, we discovered that B7-H1 high expressed GMSCs displayed significantly more immunosuppressive activity than B7-H1 low expressed GMSC both in vitro and in vivo in the CIA murine model.…”

“… 34 , 46 , 47 , 48 , 49 B7-H1 also has been shown to have considerable importance for the immunosuppressive properties of BMSCs and WJMSCs. 50 …”

Xenogeneic Humoral Immune Responses to Human Mesenchymal Stem Cells in Mice

“…S2 , Table 2 ), which can be interpreted as that new proteins had expressed on the cell surface of hMSCs following activation and acted as additional antigens. In fact, IFN-γ, used for hMSC activation in the present study, promotes the expression of several surface molecules such as HLA-ABC and HLA-DR and secretory molecules in Ad-MSCs ( 18 ), B7-H1 in UC-MSCs ( 22 ), and ICAM-1 and VCAM-1 in Ad- and UC-MSCs ( 23 ).…”

A Comparison of Proteins Expressed between Human and Mouse Adipose-Derived Mesenchymal Stem Cells by a Proteome Analysis through Liquid Chromatography with Tandem Mass Spectrometry

“…Our detection of FAP protein fragments in hADSCs in the present experiment suggested that the same mechanism may be present in hADSCs. Previous reports showed that STAT1 signaling is involved in interferon (IFN)-γ-induced immunosuppression in human bone marrow-derived mesenchymal stem cells [ 25 ]. In the present study, a STAT1 protein fragment was detected in hADSCs, suggesting that a similar mechanism may exist in hADSCs.…”