Compartmentalization, cooperation, and communication: The 3Cs of Hepatocyte zonation

The unique architecture of the liver allows for spatial compartmentalization of its functions, also known as liver zonation. In contrast to organelles and cells, this compartment is devoid of a surrounding membrane, rendering traditional biochemical tools ineffective for studying liver zonation. Recent advancements in tissue imaging and single-cell technologies have provided new insights into the complexity of tissue organization, rich cellular composition, and the gradients that shape zonation. Hepatocyte gene expression profiles and metabolic programs differ based on their location. Non-parenchymal cells further support hepatocytes from different zones through local secretion of factors that instruct hepatocyte activities. Collectively, these elements form a cohesive and dynamic network of cell-cell interactions that vary across space, time, and disease states. This review will examine the cell biology of hepatocytes in vivo, presenting the latest discoveries and emerging principles that govern tissue-level and sub-cellular compartmentalization.