小柯机器人

美国波士顿大学Valerie Gouon-Evans研究组发现，VEGFA mRNA-LNP促进急慢性肝病中胆管上皮细胞向肝细胞的转化并逆转脂肪变性和纤维化。2023年11月28日，《细胞—干细胞》杂志在线发表了这项成果。

研究人员表示，众所周知，肝脏通过肝细胞的增殖具有卓越的再生能力。然而，在慢性损伤或严重肝细胞死亡时，肝细胞的增殖能力会衰竭。

为了克服这一障碍，研究人员提出用血管内皮生长因子 A（VEGFA）作为治疗手段，加速胆管上皮细胞（BEC）向肝细胞的转化。在斑马鱼身上进行的研究证实，阻断血管内皮生长因子受体会减弱胆管上皮细胞驱动的肝脏修复，而过量表达血管内皮生长因子A则会促进肝脏修复。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）中的非整合性、安全的核苷修饰mRNA传递VEGFA，可诱导BEC向肝细胞的有力转化，并消除脂肪变性和纤维化。在人类和小鼠病变肝脏中，研究人员进一步发现了与KDR表达细胞衍生肝细胞相关的VEGFA受体KDR表达的BEC。

这项工作将KDR表达细胞（很可能是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的意外治疗效果，其安全性已通过COVID-19疫苗得到广泛验证，并可利用BEC驱动的修复来治疗肝脏疾病。

附：英文原文

Title: VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis

Author: Fatima Rizvi, Yu-Ri Lee, Ricardo Diaz-Aragon, Pushpinder S. Bawa, Juhoon So, Rodrigo M. Florentino, Susan Wu, Arianna Sarjoo, Emily Truong, Anna R. Smith, Feiya Wang, Elissa Everton, Alina Ostrowska, Kyounghwa Jung, Ying Tam, Hiromi Muramatsu, Norbert Pardi, Drew Weissman, Alejandro Soto-Gutierrez, Donghun Shin, Valerie Gouon-Evans

Issue&Volume: 2023-11-28

Abstract: 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.

DOI: 10.1016/j.stem.2023.10.008

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00392-2

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