Background and aim: Programmed death-ligand 1 (PD-L1) was involved in regulating Th17/Treg cell balance in ulcerative colitis (UC). Extracellular vesicles (EVs) from genetically modified bone marrow mesenchymal stem cells (BMSCs) can serve as a stable delivery system to overexpress PD-L1. The study was designed to evaluate the therapeutic mechanism of BMSC-EVs overexpressing PD-L1 (PD-L1-EVs) on ulcerative colitis.
Methods: Experimental model of UC was established in rats by drinking 5% dextran sulfate sodium (DSS). Apoptosis-related proteins, inflammatory response-related factors and oxidative stress related mediators were detected. Westernblot was used to detecte key proteins in the PI3K/AKT signaling pathway and its downstream effectors. The CD4+ Foxp3+ Treg cells and CD4+ IL-17A+ Th17 cells in spleen and mesenteric lymph nodes (MLNs) was detected by flow cytometry.
Results: PD-L1-EVs significantly alleviated the manifestations and pathological damage of UC rats by inhibiting the expression of IFN-γ, IL-1β, IL-8, IL-6, IL-2, BAX, NF-κB, TNF-α, MPO, and MDA, and up-regulating the expression of IL-4, BCL-2, SOD, and GSH. Furthermore, the proportions of Th17 cells were decreased and that of Treg cells were upregulated by PD-L1-EVs treatment. PTEN inhibitors (bpv) partially abolished the inhibitory effect of PD-L1-EVs on PI3K-AKT signaling and impaired the therapeutic efficacy of PD-L1-EVs.
Conclusions: PD-L1-EVs mitigated colonal inflammation, apoptosis and oxidative stress through blocking the activation of PI3K/Akt/mTOR pathway and regulating the balance of Th17/Treg cells.
Keywords: PTEN/PI3K/AKT/mTOR axis; bone marrow-derived mesenchymal stem cells; extracellular vesicles; programmed death-ligand 1; ulcerative colitis.
© 2022 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.