Introduction

Traditional in vitro liver models have limitations in mimicking the native tissue microenvironment. 3D liver models address these shortcomings by recreating the anatomical and functional features of the liver more accurately. 

Method

Human primary or stem cell-derived hepatocytes, liver endothelial cells, stellate cells and immune cells were introduced within a microfluidic setup of 64 parallel chips in a microtiter plate format. Confocal microscopy and transcriptomics were used to characterize and compare the model to native liver. We challenged the system with lipids or cytokines to induce steatotic and fibrotic phenotypes. High content confocal imaging and cytokine release measurements were used to evaluate the effect of clinically relevant tool compounds in a fully automated setup.

Results

Liver-derived endothelial cells self organized into sinusoidal-like structures, with dimension and marker expression consistent with liver sinusoidal vasculature and in close basolateral interaction with stellate cells. Hepatocytes were fully polarized and organized in distinct plate-like structures, separating interconnected endothelial vessels associated with functional macrophages. Transcriptomics analysis revealed fidelity with the diversity of gene expression levels found in liver tissue with clear representation of all major liver cell types. Steatosis and fibrosis phenotypes could be induced as presented by visible hepatic lipid accumulation, stellate cell activation marker increase and cytokine release.

Conclusion

This comprehensive liver model reflects the cellular organization and interactions found within the liver lobule in an unprecedented manner and opens new avenues to better understand the relationship between liver diseases and diabetic (e.g. obesity and insulin resistance) and non-diabetic endocrinopathies.