SHED‐exos promote saliva secretion by suppressing p‐ERK1/2‐mediated apoptosis in glandular cells

Objectives Confirm that stem cells from human exfoliated deciduous teeth‐derived exosomes (SHED‐exos) can limit inflammation‐triggered epithelial cell apoptosis and explore the molecular mechanism. Methods SHED‐exos were injected into the submandibular glands (SMGs) of non‐obese diabetic (NOD) mice, an animal model of Sjögren's syndrome (SS). Cell death was evaluated by western blotting and terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labelling staining. Results SHED‐exos treatment promoted the saliva flow rates of NOD mice, accompanied by decreased cleaved caspase‐3 levels and apoptotic cell numbers in SMGs. SHED‐exos inhibited autophagy, pyroptosis, NETosis, ferroptosis, necroptosis and oxeiptosis marker expression in SS‐damaged glands. Mechanistically, Kyoto Encyclopedia of Genes and Genomes analysis of exosomal miRNAs suggested that the rat sarcoma virus (RAS)/mitogen‐activated protein kinase kinase (MEK)/extracellular signal‐regulated kinase (ERK) pathway might play an important role. In vivo, the expression of Kirsten RAS, Harvey RAS, MEK1/2 and p‐ERK1/2 was upregulated in SMGs, and this change was blocked by SHED‐exos treatment. In vitro, SHED‐exos suppressed p‐ERK1/2 activation and increased cleaved caspase‐3 and apoptotic cell numbers, which were induced by IFN‐γ. Conclusion SHED‐exos suppress epithelial cell death, which is responsible for promoting salivary secretion. SHED‐exos inhibited inflammation‐triggered epithelial cell apoptosis by suppressing p‐ERK1/2 activation, which is involved in these effects.