Exosomal miR-103a-3p from Crohn’s Creeping Fat-Derived Adipose-Derived Stem Cells Contributes to Intestinal Fibrosis by Targeting TGFBR3 and Activating Fibroblasts

Author:

Qian Wenwei1,Xu Yihan2,Wen Weiwei1,Huang Liangyu3ORCID,Guo Zhen2ORCID,Zhu Weiming12,Li Yi12ORCID

Affiliation:

1. Department of General Surgery, Jinling Hospital, Medical School of Southeast University , No. 305 East Zhongshan Road, Nanjing , PR China

2. Department of General Surgery, Jinling Hospital, Medical School of Nanjing University , No. 305 East Zhongshan Road, Nanjing , PR China

3. Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou , PR China

Abstract

Abstract Background and Aims Mesenteric adipose tissue hypertrophy is a hallmark of Crohn’s disease [CD], and creeping fat [CF] is unique to CD. Adipose-derived stem cells [ASCs] from inflammatory tissue exhibited altered biological functions. The role of ASCs isolated from CF in intestinal fibrosis and the potential mechanism remain unclear. Methods ASCs were isolated from CF [CF-ASCs] and disease-unaffected mesenteric adipose tissue [Ctrl-ASCs] of patients with CD. A series of in vitro and in vivo experiments were conducted to study the effects of exosomes from CF-ASCs [CF-Exos] on intestinal fibrosis and fibroblast activation. A micro-RNA microarray analysis was performed. Western blot, luciferase assay and immunofluorescence were performed to further detect the underlying mechanisms. Results The results indicated that CF-Exos promoted intestinal fibrosis by activating fibroblasts in a dose-dependent manner. They continuously promoted progression of intestinal fibrosis even after dextran sulphate sodium withdrawal. Further analysis showed that exosomal miR-103a-3p was enriched in CF-Exos and participated in exosome-mediated fibroblast activation. TGFBR3 was identified as a target gene of miR-103a-3p. Mechanistically, CF-ASCs released exosomal miR-103a-3p and promoted fibroblast activation by targeting TGFBR3 and promoting Smad2/3 phosphorylation. We also found that the expression of miR-103a-3p in diseased intestine was positively associated with the degree of CF and fibrosis score. Conclusion Our findings show that exosomal miR-103a-3p from CF-ASCs promotes intestinal fibrosis by activating fibroblasts via TGFBR3 targeting, suggesting that CF-ASCs are potential therapeutic targets for intestinal fibrosis in CD.

Funder

National Natural Science Foundation of China

Publisher

Oxford University Press (OUP)

Subject

Gastroenterology,General Medicine

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