Regulation of pancreatic fibrosis by acinar cell-derived exosomal miR-130a-3p via targeting of stellate cell PPAR-γ

ABSTRACT As endogenous miRNA carriers,exosomes play a role in the pathophysiological process of various diseases. However, their functions and regulation mechanisms in pancreatic fibrosis remain unclear. In this study, an RNA microarray was used to detect differentially expressed exosomal miR-130a-3p in AR42J cells after taurolithocholate (TLC) treatment. mRNA-seq was used to screen the differentially expressed PPAR-γ after pancreatic stellate cell (PSC) activation. Fluorescence labeling of exosomes and dynamic tracing showed that exosomes can fuse with the cell membrane of PSCs and transport miR-130a-3p into PSCs. A luciferase reporter gene assay was used to confirm that miR-130a can bind to PPAR-γ to inhibit PPAR-γ expression. In vitro and in vivo functional experiments were performed for gain-of-function studies and loss-of-function studies, respectively. These studies showed that acinar cell-derived exosomal miR-130a-3p promotes PSC activation and collagen formation through targeting of cellular PPAR-γ. Knockdown of miR-130a-3p significantly improved pancreatic fibrosis. Notably, miR-130a-3p knockdown reduced serum levels of hyaluronic acid (HA) and β-amylase and increased the C-peptide to protect endocrine and exocrine pancreatic functions and the function of endothelial cells. The exosomal miR-130a-3p/PPAR-γ axis participates in the activation of PSCs and the mechanism of CP fibrosis, thus providing a potential new target for the treatment of chronic pancreatitis fibrosis.