Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
Sci Rep. 2022 Aug 18;12(1):14079. doi: 10.1038/s41598-022-18119-6.
Humanized liver rodent models, in which the host liver parenchyma is repopulated by human hepatocytes, have been increasingly used for drug development and disease research. Unlike the leading humanized liver mouse model in which Fumarylacetoacetate Hydrolase (Fah), Recombination Activating Gene (Rag)-2 and Interleukin-2 Receptor Gamma (Il2rg) genes were inactivated simultaneously, generation of similar recipient rats has been challenging. Here, using Velocigene and 1-cell-embryo-targeting technologies, we generated a rat model deficient in Fah, Rag1/2 and Il2rg genes, similar to humanized liver mice. These rats were efficiently engrafted with Fah-expressing hepatocytes from rat, mouse and human. Humanized liver rats expressed human albumin and complement proteins in serum and showed a normal liver zonation pattern. Further, approaches were developed for gene delivery through viral transduction of human hepatocytes either in vivo, or in vitro prior to engraftment, providing a novel platform to study liver disease and hepatocyte-targeted therapies.
人源化肝脏啮齿动物模型，其中宿主肝实质被人肝细胞重新填充，已越来越多地用于药物开发和疾病研究。与同时失活 fumarylacetoacetate hydrolase (Fah)、recombination activating gene (Rag)-2 和 interleukin-2 receptor gamma (Il2rg) 基因的领先人源化肝脏小鼠模型不同，类似的受体大鼠的生成颇具挑战性。在这里，我们使用 Velocigene 和单细胞胚胎靶向技术，生成了一种 Fah、Rag1/2 和 Il2rg 基因缺失的大鼠模型，类似于人源化肝脏小鼠。这些大鼠能够有效地接受来自大鼠、小鼠和人类表达 Fah 的肝细胞的移植。人源化肝脏大鼠在血清中表达人白蛋白和补体蛋白，并表现出正常的肝脏分区模式。此外，还开发了通过病毒转导将人肝细胞在体内或在移植前进行体外基因传递的方法，为研究肝脏疾病和肝细胞靶向治疗提供了一个新的平台。
