Liver‐humanized mice: A translational strategy to study metabolic disorders

Abstract

The liver is the metabolic core of the whole body. Tools commonly used to study the human liver metabolism include hepatocyte cell lines, primary human hepatocytes, and pluripotent stem cells-derived hepatocytes in vitro, and liver genetically humanized mouse model in vivo. However, none of these systems can mimic the human liver in physiological and pathological states satisfactorily. Liver-humanized mice, which are established by reconstituting mouse liver with human hepatocytes, have emerged as an attractive animal model to study drug metabolism and evaluate the therapeutic effect in "human liver" in vivo because the humanized livers greatly replicate enzymatic features of human hepatocytes. The application of liverhumanized mice in studying metabolic disorders is relatively less common due to the largely uncertain replication of metabolic profiles compared to humans. Here, we summarize the metabolic characteristics and current application of liver-humanized mouse models in metabolic disorders that have been reported in the literature, trying to evaluate the pros and cons of using liver-humanized mice as novel mouse models to study metabolic disorders.

The changing landscape of drug clinical trials on cardiometabolic diseases in China, 2009–2021

“…Inclisiran, a siRNA targeting PCSK9, has already been registered for two trials in China. Also, many new technologies may bring breakthroughs including high-throughput screening platforms (small molecules and natural products), multi-omics technology, artificial intelligence (AI) technology, [ 56 , 57 ] human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM), [ 58 , 59 ], 3D bioprinting organoid, [ 60 , 61 ] and the humanized genetic modified models, [ 62 , 63 ]. which may greatly reduce the cost and risk of new drugs before the clinical trials.…”

The 3Rs in Experimental Liver Disease

“…Metabolism is considered to be more active in murine models, being exemplified in the expansion of metabolic enzyme genes and their respective increased production [32,33]. Remarkably, these distinctions are further exemplified in omics analyses that highlight partially divergent genomic responses to liver injury and disease progression [34,35], ultimately indicating that improved models, such as humanized mice, could reduce the gap between the two species [36]. This image was created using Biorender platform.…”