TNF-α preconditioned UCMSCs-derived EVs enhance the inhibition of necroptosis of acinar cells in SAP

Severe acute pancreatitis (SAP) is a common abdominal emergency with a high mortality rate and a lack of effective therapeutic options. Although mesenchymal stem cells (MSCs) 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 (NaT) was used to induce a rat SAP model via retrograde injection into the common biliopancreatic duct. After 72 hours of EVs transplantation, pancreatic pathological damage was alleviated, along with a decrease in serum amylase activity and pro-inflammatory cytokines levels. Interestingly, when UCMSCs were preconditioned with 10ng/mL TNF-α for 48h, 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 via RIPK3/MLKL axis. In conclusion, our study demonstrated that TNF-α-EVs was 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.

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