Exosomal miR-140-3p and miR-143-3p from TGF-β1-treated pancreatic stellate cells target BCL2 mRNA to increase β-cell apoptosis

Background: People with chronic pancreatitis (CP) normally develop a fibrotic pancreas with reduced beta-cell mass. Limited studies have focused on the development and pathogenesis of CP-related diabetes. MiRNAs packaged as exosomes are the key regulators of beta-cell dysfunction. This study aimed to define the effect of exosomal miRNA from activated pancreatic stellate cells (PSCs) on beta-cells. Methods: Exosomes in the supernatants of mouse PSCs lines were extracted via ultracentrifugation and then identified. The role of exosomes secreted by transforming growth factor-beta 1 (TGF-beta 1)-treated PSCs in beta-cell function was assessed. MiRNAs were prepared from exosomes extracted from TGF-beta 1-treated and untreated PSCs (T-Exo or C-Exo), and the miRNA expression profiles were compared by microarray. Then, miR-140-3p and miR143-3p were overexpressed or inhibited in MIN6 cells and islets to determine their molecular and functional effects. Results: Exosomes were the predominant extracellular vesicles secreted by PSCs into the culture medium. The MIN6 cells incubated with T-Exo had less insulin secretion and lower viability than the MIN6 cells incubated with PBS or C-Exo. MiR-140-3p and miR-143-3p were notably upregulated in T-Exo. Enhancing the expression of miR-140-3p and miR-143-3p in beta-cells decreased the cell count and viability and increased the cleaved caspase-3 levels. Mechanistically, T-Exo mediated the intercellular transfer of miR-140-3p and miR-143-3p by targeting the B-cell lymphoma 2 gene in recipient beta-cells to induce cell death. Conclusions: Exosomal miRNA transfer as a communication mode between PSCs and beta-cells, which may be explored for its therapeutic utility.

Automated summary

This study reveals the impact of exosomal miRNA secreted by activated pancreatic stellate cells (PSCs) on beta-cell function. Specifically, the miR-140-3p and miR-143-3p in these exosomes induce cell death in beta-cells by targeting the B-cell lymphoma 2 gene. The findings highlight the communication mode between PSCs and beta-cells through exosomal miRNA transfer and offer potential therapeutic strategies.