Restricted accessResearch articleFirst published online 2023-12
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.
Impact statement
Mesenchymal stem cells (MSCs) are ideal seed cells for repairing damage in many diseases. Paracrine secretion is an important pathway for MSCs to achieve therapeutic effects, and MSC-derived extracellular vesicles (EVs) have been shown to provide similar functions to MSCs. However, the therapeutic effect of EVs on severe acute pancreatitis (SAP) is unclear. In this study, we demonstrated that umbilical cord mesenchymal stem cell (UCMSC)-derived EVs alleviated SAP injury by inhibiting necroptosis of acinar cells. More importantly, EVs derived from tumor necrosis factor alpha preconditioned UCMSCs exerted enhanced efficacy. The outcomes of the work provide evidence for EVs as a cell-free therapy strategy for SAP.
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