Humanized liver mouse models are increasingly being used in preclinical trials and have allowed for groundbreaking in-vivo research to evaluate everything from human-specific drug toxicity and efficacy to gene therapies. Unlike their transgenic mouse model counterparts, chimeric liver mouse models that include human hepatocytes and it is important for researchers to better understand the interactions between the implanted human cells and native mouse cells especially for drug metabolism studies.

 

In a recent study by Chow et al published in The Journal of Pharmacology and Experimental Therapeutics, it was shown that as a result of the species mismatch between human and mouse cells certain deficiencies are increasingly common, including dysregulation of hepatocyte proliferation and bile acid homeostasis in hFRGN livers that led to hepatotoxicity, gallbladder distension, liver deformity and other extrahepatic changes. “Although the nuclear receptors in human and other species share common targets, species difference in nuclear receptor activation exists”, and Chow et al suggest that additional research may be necessary to fully understand the inter-organ communication between human and mouse organs in h-chimeric mice.

 

Specifically, the miscommunication between human hepatocytes and murine stellate cells (which typically signal to hepatocytes to stop proliferating) is an important consideration. When this occurs, intracellular spaces are frequently reduced and cholangiocyte growth is inhibited, which can result in reduced bile flow as well as increased bile acid accumulation and toxicity.
Although we do not believe that any of these factors are reason enough to discontinue the use of humanized mouse or rat models for preclinical research, Chow et al do point out the need for increased awareness and the importance of addressing these deficiencies when reporting data in human drug metabolism studies.