Mesenchymal Stem Cell‐Derived Extracellular Vesicles with High PD‐L1 Expression for Autoimmune Diseases Treatment

Abstract

Autoimmune diseases are the third most common disease influencing the quality of life of many patients. Here, a programmed cell death‐ligand 1 + (PD‐L1) mesenchymal stem cell (MSC) derived extracellular vesicles (MSC‐sEVs‐PD‐L1) using lentivirus‐mediated gene transfection technology is developed for reconfiguration of the local immune microenvironment of affected tissue in autoimmune diseases. MSC‐sEVs‐PD‐L1 exhibits an impressive ability to regulate various activated immune cells to an immunosuppressed state in vitro. More importantly, in dextran sulfate sodium‐induced ulcerative colitis (UC) and imiquimod‐induced psoriasis mouse models, a significantly high accumulation of MSC‐sEVs‐PD‐L1 is observed in the inflamed tissues compared to the PD‐L1+ MSCs. Therapeutic efficiency in both UC and psoriasis mouse disease models is demonstrated using MSC‐sEVs‐PD‐L1 to reshape the inflammatory ecosystem in the local immune context. A technology is developed using MSC‐sEVs‐PD‐L1 as a natural delivery platform for autoimmune diseases treatment with high clinical potential.

Improving the immunomodulatory function of mesenchymal stem cells by defined chemical approach

“…Since the application value of MSCs lies in clinical treatment, the safety of the method is particularly important when developing improved technologies. Several studies have been published in which MSCs have been genetically modified based on viral transfection techniques (38)(39)(40). Although these methods can directly transform MSCs, the off-target effects associated with genetic modification and the safety of residual vectors such as viruses still pose a major obstacle to clinical transformation.…”

Mesenchymal stem/stromal cells in the pathogenesis and regenerative therapy of inflammatory bowel diseases

“…The regulation of immune checkpoint pathway plays pivotal roles in the treatment of immune system diseases ( 85 ). Among them, the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) checkpoint pathway is one of the important components to inhibit the immune response and maintain immune homeostasis ( 86 ). PD-1, a costimulatory molecule, is induced to be expressed on the surface of activated T cells, B cells and NK cells.…”

Mesenchymal stem cells-based therapy in liver diseases

“…Chen et al earlier investigated the therapeutic effect of bone marrow MSCs (BM-MSCs) transplantation in experimental autoimmune hepatitis (EAH) in mice and showed that BMSCs transplantation, especially multi-dose transplantation, increased hepatic PD-L1 levels along with decreased IL-17 levels, producing immunosuppressive effects [ 436 ]. Similarly, a recent study used lentiviral transfection to construct PD-L1-high expressing MSCs-EVs, which successfully initiated immunosuppressive signaling in activated immune cells, including T cells, macrophages and DCs, by interacting with PD-1 on the surface of these cells [ 437 ]. By constructing mouse autoimmune disease models of ulcerative colitis and psoriasis, this study further revealed that extracellular vesicles with high PD-L1 expression could specifically target liver lesion sites and effectively modulate the balance between Th1, Th2, Th17 and Treg cells subsets to attenuate autoimmune responses in AIH [ 437 ].…”

“…Similarly, a recent study used lentiviral transfection to construct PD-L1-high expressing MSCs-EVs, which successfully initiated immunosuppressive signaling in activated immune cells, including T cells, macrophages and DCs, by interacting with PD-1 on the surface of these cells [ 437 ]. By constructing mouse autoimmune disease models of ulcerative colitis and psoriasis, this study further revealed that extracellular vesicles with high PD-L1 expression could specifically target liver lesion sites and effectively modulate the balance between Th1, Th2, Th17 and Treg cells subsets to attenuate autoimmune responses in AIH [ 437 ].…”