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Location, Location, Location—Cell Position in Maintaining and Regenerating Liver

New research in mice has identified which cells of the liver contribute in large part toward maintaining the organ or regenerating it after injury. The liver is unique by virtue of its ability to regenerate and adjust its size in proportion to overall body size. At the microscopic level, the liver tissue is arranged in a honeycomb pattern with repeating hexagonal structures called lobules. These structures are made up of a central vein surrounded at each of the six outer points by a bundle consisting of a portal vein, hepatic artery, and bile duct. Lobule geography is mapped accordingly based on these landmarks into three areas, or “zones.” The same liver cell type can have unique capabilities depending on its zonal position, such as production of specific metabolic enzymes.

Scientists applied advanced genetic tools to answer a question that had conflicting results in the past: do cells in one zone contribute more to liver growth and regeneration than others? Using state-of-the-art gene editing technology, they generated 11 new strains of mice with modifications to switch on a fluorescent marker that selectively labels different groups of cells in the three zones of the liver lobule. In these mice and three other similar models, they tracked the abundance of new cells descended from the marked cells in these three zones. Under conditions of either normal day-to-day growth or regeneration after injury from two different toxins, cells in zone 2 showed the greatest increases in number to maintain or restore the liver. The researchers hypothesize that these cells may be more protected from insults coming from the circulation or bile ducts. Next, the researchers further probed how the zone 2 cells are better able to help the liver grow and regenerate by identifying which genes were ramped up or suppressed to support liver cell growth. They identified a cellular signaling pathway that is involved in the growth of these zone 2 cells, which could be important for the development of potential therapeutics. This work provides compelling evidence for the importance of cellular positioning within the liver lobule, particularly in zone 2, in maintaining equilibrium within the organ and replenishing it after injury. Future studies could help to define the role of these cells in liver disease and inform therapeutic strategies to boost liver regeneration.

Wei Y, Wang YG, Jia Y,...Zhu H. Liver homeostasis is maintained by midlobular zone 2 hepatocytes. Science 371: eabb1625, 2021.