Tumor Necrosis Factor Alpha Preconditioned Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles Enhance the Inhibition of Necroptosis of Acinar cells in Severe Acute Pancreatitis

Severe acute pancreatitis (SAP) is a common abdominal emergency with a high mortality rate and a lack of effective therapeutic options. Although mesenchymal stem cell (MSC) transplantation is a potential treatment for SAP, the mechanism remains unclear. It has been suggested that MSCs may act mainly through paracrine effects; therefore, we aimed to demonstrate the therapeutic efficacy of extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (UCMSCs) for SAP. Na-taurocholate was used to induce a rat SAP model through retrograde injection into the common biliopancreatic duct. After 72 h of EVs transplantation, pancreatic pathological damage was alleviated, along with a decrease in serum amylase activity and pro-inflammatory cytokine levels. Interestingly, when UCMSCs were preconditioned with 10 ng/mL tumor necrosis factor alpha (TNF-α) for 48 h, the obtained EVs (named TNF-α-EVs) performed an enhanced efficacy. Furthermore, both animal and cellular experiments showed that TNF-α-EVs alleviated the necroptosis of acinar cells of SAP through RIPK3/MLKL axis. In conclusion, our study demonstrated that TNF-α-EVs were able to enhance the therapeutic effect on SAP by inhibiting necroptosis compared to normal EVs. This study heralds that TNF-α-EVs may be a promising therapeutic approach for SAP in the future.