Table2_Bone marrow mesenchymal stem cell-derived small extracellular vesicles promote liver regeneration via miR-20a-5p/PTEN.XLS

Balancing hepatocyte death and proliferation is key to non-transplantation treatments for acute liver failure (ALF), which has a high short-term mortality rate. Small extracellular vesicles (sEVs) may act as mediators in the repair of damaged liver tissue by mesenchymal stem cells (MSCs). We aimed to investigate the efficacy of human bone marrow MSC-derived sEVs (BMSC-sEVs) in treating mice with ALF and the molecular mechanisms involved in regulating hepatocyte proliferation and apoptosis. Small EVs and sEV-free BMSC concentrated medium were injected into mice with LPS/D-GalN-induced ALF to assess survival, changes in serology, liver pathology, and apoptosis and proliferation in different phases. The results were further verified in vitro in L-02 cells with hydrogen peroxide injury. BMSC-sEV-treated mice with ALF had higher 24 h survival rates and more significant reductions in liver injury than mice treated with sEV-free concentrated medium. BMSC-sEVs reduced hepatocyte apoptosis and promoted cell proliferation by upregulating miR-20a-5p, which targeted the PTEN/AKT signaling pathway. Additionally, BMSC-sEVs upregulated the mir-20a precursor in hepatocytes. The application of BMSC-sEVs showed a positive impact by preventing the development of ALF, and may serve as a promising strategy for promoting ALF liver regeneration. miR-20a-5p plays an important role in liver protection from ALF by BMSC-sEVs.

维持肝细胞死亡与增殖的动态平衡是急性肝衰竭（ALF）非移植治疗的核心靶点，而急性肝衰竭具有极高的短期死亡率。细胞外小囊泡（sEVs）可能介导间充质干细胞（MSCs）修复受损肝组织。本研究旨在探讨人骨髓间充质干细胞来源的细胞外小囊泡（BMSC-sEVs）对脂多糖（LPS）/D-氨基半乳糖（D-GalN）诱导的急性肝衰竭小鼠的治疗效果，及其调控肝细胞增殖与凋亡的分子机制。我们将细胞外小囊泡及无细胞外小囊泡的间充质干细胞浓缩培养基注射入脂多糖/D-氨基半乳糖诱导的急性肝衰竭小鼠体内，评估小鼠生存率、血清学指标变化、肝脏病理学特征，以及不同阶段的肝细胞凋亡与增殖情况。上述实验结果还在过氧化氢损伤的L-02细胞中进行了体外验证。与无细胞外小囊泡的浓缩培养基处理组相比，经BMSC-sEVs处理的急性肝衰竭小鼠24小时生存率更高，肝损伤程度也得到更显著的改善。BMSC-sEVs可通过上调靶向PTEN/AKT信号通路的miR-20a-5p，抑制肝细胞凋亡并促进细胞增殖。此外，BMSC-sEVs还可在肝细胞中上调miR-20a前体的表达。本研究证实，BMSC-sEVs的应用可有效阻断急性肝衰竭的进展，有望成为促进急性肝衰竭肝脏再生的潜在治疗策略，而miR-20a-5p在BMSC-sEVs介导的急性肝衰竭肝脏保护过程中发挥了关键作用。