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Human Adipose Mesenchymal Stem Cell-derived Exosomes Protect Mice from DSS-Induced Inflammatory Bowel Disease by Promoting Intestinal-stem-cell and Epithelial Regeneration.

ABSTRACT: Inflammatory bowel disease (IBD) remains a severe disease for most patients, with its incidence and prevalence increasingly globally. Currently, there is no effective treatments for IBD, and traditional treatments have multiple side effects. Therefore, novel therapeutic strategies or alternative drugs are urgently needed. Previous studies have shown that mesenchymal stem cell-derived exosomes have exhibited promising therapeutic effects on inflammatory disease. Here, we performed intravenous injection of human adipose mesenchymal stem cell (hADSC)-derived exosomes (hADSC-Exo) in a DSS-induced IBD mouse model and found that hADSC-Exo promoted functional recovery, downregulated inflammatory responses, reduced intestine cell apoptosis, increased epithelial regeneration and maintained intestinal barrier integrity. Moreover, we established a colon organoid, hADSC-Exo and TNF-α co-cultured system to explore the protective effect of hADSC-Exo on integrity of intestine mucosa and epithelial regeneration. We showed that hADSC-Exo not only can promote the proliferation and regeneration of Lgr5⁺ ISCs and epithelial cells but also ameliorate the inflammation damage in TNF-α induced inflammatory damaged mice colon organoids. Taken together, our findings indicate that hADSC-Exo protects intestine integrity, activates intestine epithelial cell and ISCs proliferation, suggesting that hADSC-Exo might be a potential effective treatment approach for IBD. We also provide a theoretical basis for new therapeutic strategies for cell-free therapy in inflammatory bowel disease.

SUBMITTER: Yu H

PROVIDER: S-EPMC8407880 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundEfficient and stable delivery of neurotrophic factors (NTFs) is crucial to provide suitable microenvironment for peripheral nerve regeneration. Neurotrophin-3 (NT-3) is an important NTF during peripheral nerve regeneration which is scarce in the first few weeks of nerve defect. Exosomes are nanovesicles and have been served as promising candidate for biocarrier. In this work, NT-3 mRNA was encapsulated in adipose-derived stem cell (ADSC)-derived exosomes (ExoNT-3). These engineered exosomes were applied as NT-3 mRNA carrier and then were loaded in nerve guidance conduit (ExoNT-3-NGC) to bridge rat sciatic nerve defect.MethodNT-3 mRNA was encapsulated in exosomes by forcedly expression of NT-3 mRNA in the donor ADSCs. ExoNT-3 were co-cultured with SCs in vitro; after 24 h of culture, the efficiency of NT-3 mRNA delivery was evaluated by qPCR, western blotting and ELISA. Then, ExoNT-3 were loaded in alginate hydrogel to construct the nerve guidance conduits (ExoNT-3-NGC). ExoNT-3-NGC were implanted in vivo to reconstruct 10 mm rat sciatic nerve defect. The expression of NT-3 was measured 2 weeks after the implantation operation. The sciatic nerve functional index (SFI) was examined at 2 and 8 weeks after the operation. Moreover, the therapeutic effect of ExoNT-3-NGC was also evaluated by morphology assay, immunofluorescence staining of regenerated nerves, function evaluation of gastrocnemius muscles after 8 weeks of implantation.ResultsThe engineered exosomes could deliver NT-3 mRNA to the recipient cells efficiently and translated into functional protein. The constructed NGC could realize stable release of exosomes at least for 2 weeks. After NGC implantation in vivo, ExoNT-3-NGC group significantly promote nerve regeneration and improve the function recovery of gastrocnemius muscles compared with control exosomes (Exoempty-NGC) group.ConclusionIn this work, NGC was constructed to allow exosome-mediated NT-3 mRNA delivery. After ExoNT-3-NGC implantation in vivo, the level of NT-3 could restore which enhance the nerve regeneration. Our study provide a potential approach to improve nerve regeneration.

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Human Adipose Mesenchymal Stem Cell-derived Exosomes Protect Mice from DSS-Induced Inflammatory Bowel Disease by Promoting Intestinal-stem-cell and Epithelial Regeneration.

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