肝移植治疗终末期肝病一直面临着供肝匮乏的难题，干细胞研究的兴起为解决这一难题提供了新思路。但干细胞体外分化得到的肝细胞存在数量、功能等方面的诸多缺陷，难以完全模拟复杂的肝脏功能。课题组前期建立了遗传距离最远的异种嵌合体，证实该嵌合体是研究干细胞体内分化特性、构建完整组织器官的良好模型，为干细胞体内分化再生肝脏提供了重要依据。据此,本研究拟利用课题组建立的基于CRISPR-Cas9基因编辑技术的延胡索酸乙酰乙酸水解酶（FAH）基因敲除的肝损伤食蟹猴模型，研究食蟹猴和人多能干细胞来源的肝祖细胞（HPC）参与肝脏嵌合发育和再生修复受损肝脏的能力，评价HPC分化阶段和植入数量对肝脏再生的影响，进而探讨利用嵌合肝进行肝移植的可能性。该研究不仅有助于阐明干细胞的体内肝分化的机制，为肝移植或肝细胞移植提供新的供肝或细胞来源，也为进一步利用动物在体生产人类组织器官提供理论依据。

Liver transplantation (LT) is regarded as the only effective treatment for end stage liver diseases. However, the critical shortage of liver grafts greatly hampered the progress of LT. During the past two decades, great progress has been made in stem cell field, which provides an innovative strategy to solve the problem of severe donor shortage. Hepatocytes or hepatic-like cells derived from pluripotent stem cell in vitro exhibit liver function to some extent, but could not completely restore liver function due to insufficient quantity and incompetent function. To generate humanized hepatocytes or parts of liver in non-human primate animal models could be a promising countermeasure. In our previous study, our group established a chimera animal model between two divergent species. Furthermore, we established a protocol to generate hepatic progenitor cells from human pluripotent stem cells efficiently. The above studies lay a solid theoretical foundation and provide technology support to generate organs in a heterologous chimera. A FAH (fuarylacetoacetat hydrolase) knockout cynomolgus monkey model was successfully established by our group. In the present study, we plan to generate a chimeric liver by transplanting human pluripotent stem cell derived hepatic progenitor cell into the early stage of embryonic liver of FAH knockout cynomolgus monkey through utero cell transplantation under ultrasound guidance. We will delineate the fate of human HPCs during the liver development. Meanwhile, we try to figure out the optimal quantity, frequency as well as injection routes of HPCs transplantation. The research is not only conducive to illuminating the mechanism of stem cell differentiation in vivo and the process of liver organogenesis, but also could provide a new avenue of generating humanized cells, tissue and organ in vivo for disease research and treatment.