Fumarylacetoacetate hydrolase gene as a knockout target for hepatic chimerism and donor liver production

A reliable source of human hepatocytes and transplantable livers is needed. Interspecies embryo complementation, which involves implanting donor human stem cells into early morula/blastocyst stage animal embryos, is an emerging solution to the shortage of transplantable livers. We review proposed mutations in the recipient embryo to disable hepatogenesis, and discuss the advantages of using fumarylacetoacetate hydrolase knockouts and other genetic modifications to disable hepatogenesis. Interspecies blastocyst complementation using porcine recipients for primate donors has been achieved, although percentages of chimerism remain persistently low. Recent investigation into the dynamic transcriptomes of pigs and primates have created new opportunities to intimately match the stage of developing animal embryos with one of the many varieties of human induced pluripotent stem cell. We discuss techniques for decreasing donor cell apoptosis, targeting donor tissue to endodermal structures to avoid neural or germline chimerism, and decreasing the immunogenicity of chimeric organs by generating donor endothelium. In this article, Nyberg and colleagues discuss the possibility of generating human livers through interspecies blastocyst complementation, review candidate hepatogenesis-disabling mutations in recipient blastocysts with a focus on fumarylacetoacetate hydrolase knockouts as an advantageous model, and present recent advances in blastocyst complementation to improve the effectiveness and ethics of interspecies hepatogenesis.