The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial-cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via nonintegrative and safe nucleoside-modified mRNA encapsulated into lipid nanoparticles (mRNA-LNPs) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and elimination of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This work defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals unexpected therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases.

肝脏因其通过肝细胞增殖而具有显着的再生能力而闻名。然而，在慢性损伤或严重肝细胞死亡期间，肝细胞的增殖就会耗尽。为了克服这一障碍，我们建议使用血管内皮生长因子 A (VEGFA) 作为加速胆管上皮细胞 (BEC) 向肝细胞转化的治疗手段。对斑马鱼的研究表明，阻断 VEGF 受体会消除 BEC 驱动的肝脏修复，而 VEGFA 过度表达则会促进这种修复。在急性或慢性损伤的小鼠肝脏中，通过封装在脂质纳米颗粒 (mRNA-LNP) 中的非整合且安全的核苷修饰 mRNA 递送 VEGFA，可诱导 BEC 向肝细胞的强劲转化，并消除脂肪变性和纤维化。在人类和小鼠患病肝脏中，我们进一步鉴定了与表达 KDR 的细胞源性肝细胞相关的表达 VEGFA 受体 KDR 的 BEC。这项工作将表达 KDR 的细胞（最有可能是 BEC）定义为兼性祖细胞。这项研究揭示了通过核苷修饰的 mRNA-LNP 传递 VEGFA 的意想不到的治疗益处，其安全性已通过 COVID-19 疫苗得到广泛验证，可利用 BEC 驱动的修复来潜在治疗肝脏疾病。