Engineered culture platforms to uncover synergies between microenvironmental cues in modulating liver zonation

ABSTRACT Hepatocytes exhibit compartmental (zonated) functions along the sinusoid with as many as 50% of liver genes thought to be zonated. The initiation and progression of several diseases can show a zonated bias including drug-induced liver injury, non-alcoholic fatty liver disease, and hepatocellular carcinoma. The fetal liver is not

zonated and thus zonation begins after birth due to gradients of O2, hormones, nutritional stimuli, and non- parenchymal cell (NPC) secretions acting on common pathways. As complementary tools to live animal studies, in vitro hepatocyte +/- NPC cultures subjected to specific factor gradients within fluidic devices can enable a

more detailed understanding of the regulators and functional outcomes of zonation. However, previous in vitro platforms/studies have only been able to recapitulate limited features and an incomplete understanding of hepatic zonation. We have pioneered a droplet microfluidics platform for the high-throughput generation of

reproducibly-sized 3D extracellular matrix (ECM) microgels (