Liver Acinus Dynamic Chip for Assessment of Drug-Induced Zonal Hepatotoxicity.

Abstract

Zonation along the liver acinus is considered a key feature of liver physiology. Here, we developed a liver acinus dynamic (LADY) chip that recapitulates a key functional structure of the liver acinus and hepatic zonation. Corresponding to the blood flow from portal triads to the central vein in vivo, gradual flow of oxygen and glucose–carrying culture medium into the HepG2 cell chamber of the LADY chip generated zonal protein expression patterns in periportal (PP) zone 1 and perivenous (PV) zone 3. Higher levels of albumin secretion and urea production were obtained in a HepG2/HUVECs co-culture LADY chip than in HepG2 mono-culture one. Zonal expression of PEPCK as a PP marker and CYP2E1 as a PV marker was successfully generated. Cell death rate of the PV cells was higher than that of the PP cells since zonal factors responsible for metabolic activation of acetaminophen (APAP) were highly expressed in the PV region. We also found the co-culture enhanced metabolic capacity to process APAP, thus improving resistance to APAP toxicity, in comparison with HepG2 mono-culture. These results indicate that our LADY chip successfully represents liver zonation and could be useful in drug development studies as a drug-induced zonal hepatotoxicity testing platform.