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

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. Key words:Inflammatory bowel disease (IBD), Human adipose mesenchymal stem cell (hADSC), Exosome, intestinal stem cell (ISC), epithelial cell Inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) is a chronic, nonspecific inflammatory disorder, which severely threatens the human health [1,2].IBD causes destruction of epithelial lining of the gut, which greatly impairs the life quality of most patients.Multiple causes, such as environmental, genetic, and inflammatory factors, may contribute to pathogenesis of IBD.Among these factors, epithelial dysfunction and crypt destruction play a defining role in the process of IBD [3,4].Despite recent progress in IBD research, there is still no effective clinical treatment strategy for IBD.Conventional treatment options for IBD include anti-inflammatory medications (5-amino salicylic acid, steroids) and immune-