Abstract
BackgroundHuman umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes are recognized as novel cell-free therapeutic agents for inflammatory bowel disease (IBD), a condition caused by dysregulated intestinal mucosal immunity. In this event, macrophage pyroptosis, a process of cell death following the activation of NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammasomes, is believed to partially account for inflammatory reactions. However, the role of macrophage pyroptosis in the process of hucMSC-derived exosomes alleviating colitis remains unknown. This study aimed at exploring the therapeutic effect and mechanism of hucMSC-derived exosomes on colitis repair.MethodsIn vivo, we used BALB/c mice to establish a dextran sulfate sodium (DSS)-induced colitis model and administrated hucMSC-derived exosomes intravenously to estimate its curative effect. Human myeloid leukemia mononuclear (THP-1) cells and mouse peritoneal macrophages (MPMs) were stimulated with lipopolysaccharides (LPS) and Nigericin to activate NLRP3 inflammasomes, which simulated an inflammation environment in vitro. A microRNA mimic was used to verify the role of miR-378a-5p/NLRP3 axis in the colitis repair.ResultshucMSC-derived exosomes inhibited the activation of NLRP3 inflammasomes in the mouse colon. The secretion of interleukin (IL)-18, IL-1β, and Caspase-1 cleavage was suppressed, resulting in reduced cell pyroptosis. The same outcome was observed in the in vitro cell experiments, where the co-culture of THP-1 cells and MPMs with hucMSC-derived exosomes caused decreased expression of NLRP3 inflammasomes and increased cell survival. Furthermore, miR-378a-5p was highly expressed in hucMSC-derived exosomes and played a vital function in colitis repair.ConclusionhucMSC-derived exosomes carrying miR-378a-5p inhibited NLRP3 inflammasomes and abrogated cell pyroptosis to protect against DSS-induced colitis.
Highlights
Human umbilical cord mesenchymal stem cell-derived exosomes are recognized as novel cell-free therapeutic agents for inflammatory bowel disease (IBD), a condition caused by dysregulated intestinal mucosal immunity
Characterization of Human umbilical cord mesenchymal stem cells (hucMSCs)-derived exosomes The identity and purity of nanoparticles were determined by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and western blot
The results of NTA and TEM showed that hucMSC-derived exosomes exhibited a typical vesicle structure with an average diameter of approximately 110 nm (Fig. 1A, B)
Summary
Human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes are recognized as novel cell-free therapeutic agents for inflammatory bowel disease (IBD), a condition caused by dysregulated intestinal mucosal immunity. In this event, macrophage pyroptosis, a process of cell death following the activation of NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammasomes, is believed to partially account for inflammatory reactions. IBD, encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is a complex chronic inflammatory disorder associated with multiple pathogenic factors including environmental changes, genetic susceptibility, qualitative and quantitative abnormal gut microbiota, and dysregulated immune response [1, 2]. Macrophages are increasingly recognized as the gatekeepers of intestinal immune homeostasis and it has been considered as a novel target to develop new therapies [7]
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