Abstract
Acute liver failure (ALF) is a life-threatening condition. Cell-based and cell-free-based therapies have proven to be effective in treating ALF; however, their clinical application is limited by cell tumorigenicity and extracellular vesicle (EV) isolation in large doses. Here, we explored the effectiveness and mechanism of umbilical cord mesenchymal stem cells (hUCMSCs)-based bioartificial liver (hUCMSC-BAL), which is a simple and efficient strategy for ALF. D-galactosamine-based pig and mouse ALF models were used to explore the effectiveness of hUCMSC-BAL and hUCMSC-sEV therapies. Furthermore, high-throughput sequencing, miRNA transcriptome analysis, and western blot were performed to clarify whether the miR-139-5p/PDE4D axis plays a critical role in the ALF model in vivo and in vitro. hUCMSC-BAL significantly reduced inflammatory responses and cell apoptosis. hUCMSC-sEV significantly improved liver function in ALF mice and enhanced the regeneration of liver cells. Furthermore, hUCMSC-sEV miRNA transcriptome analysis showed that miR-139-5p had the highest expression and that PDE4D was one of its main target genes. The sEV miR-139-5p/PDE4D axis played a role in the treatment of ALF by inhibiting cell apoptosis. Our data indicate that hUCMSC-BAL can inhibit cytokine storms and cell apoptosis through the sEV miR-139-5p/PDE4D axis. Therefore, we propose hUCMSC-BAL as a therapeutic strategy for patients with early ALF.