Hair follicle-MSC-derived small extracellular vesicles as a novel remedy for acute pancreatitis.

Abstract

Hair follicle-derived mesenchymal stem cell (HF-MSC)-based therapies protect against acute pancreatitis (AP). However, accumulating evidence suggests that MSC-based therapy mainly involves the secretion of MSC-derived small extracellular vesicles (MSC-sEVs) through paracrine effects. Thus, the present research investigated the therapeutic effect of HF-MSC-sEVs in AP and the underlying mechanisms. SEVs were purified from cultured HF-MSC supernatant. The effects of sEVs in vitro were analyzed on caerulein-simulated pancreatic acinar cells (PACs). The therapeutic potential of sEVs in vivo was examined in a caerulein-induced AP model. The organ distribution of sEVs in mice was determined by near-infrared fluorescence (NIRF) imaging. Serum specimens and pancreatic tissues were collected to analyze the inhibition of inflammation and pyroptosis in vivo, as well as the appropriate infusion route: intraperitoneal (i.p.) or intravenous (i.v.) injection. HF-MSC-sEVs were taken up by PACs and improved cell viability in vitro. In vivo, sEVs were abundant in the pancreas, and the indicators of pancreatitis, including amylase, lipase, the inflammatory response, myeloperoxidase (MPO) expression and histopathology scores, in sEV-treated mice were markedly improved compared with those in the AP group, especially via tail vein injection. Furthermore, we revealed that sEVs observably downregulated the levels of crucial pyroptosis proteins in both PACs and AP tissue. We innovatively demonstrated that HF-MSC-sEVs could alleviate inflammation and pyroptosis in PACs in AP, suggesting a refreshing cell-free remedy for AP.