Exosomes from TNF-α preconditioned human umbilical cord mesenchymal stromal cells inhibit the autophagy of acinar cells of severe acute pancreatitis via shuttling bioactive metabolites.

ABSTRACT

Severe acute pancreatitis (SAP) is a common critical disease of the digestive system, with high mortality and a lack of effective prevention and treatment measures. Despite mesenchymal stromal cell transplantation having the potential to treat SAP, its clinical application prospect is limited, and the mechanism is unclear. Here, we reveal the therapeutic role of exosomes from TNF-α-preconditioned human umbilical cord mesenchymal stromal cells (HUCMSCs) in attenuating SAP and show that it is partly dependent on exosomal metabolites. Bioactive metabolomics analysis showed that 48 metabolites be significantly differentially expressed between the two groups (Exo-Ctrl group versus Exo-TNF-α group). Then, the further functional experiments indicated that 3,4-dihydroxyphenylglycol could be a key molecule mediating the therapeutic effect of TNF-α-preconditioned HUCMSCs. The animal experiments showed that 3,4-dihydroxyphenylglycol reduced inflammation and oxidative stress in the pancreatic tissue and inhibited acinar cell autophagy in a rat model of SAP. Mechanistically, we revealed that 3,4-dihydroxyphenylglycol activated the mTOR pathway to inhibit acinar cell autophagy and alleviate SAP. In summary, our study demonstrated that exosomes from TNF-α-preconditioned HUMSCs inhibit the autophagy of acinar cells of SAP by shuttling 3,4-dihydroxyphenylglycol and inhibiting the mTOR pathway. This study revealed the vital role and therapeutic potential of metabolite-derived exosomes in SAP, providing a new promising method to prevent and therapy SAP.