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Zone 2 Cells Play Key Role in Liver Homeostasis, Regeneration

NEW YORK (Reuters Health) – Zone 2 liver cells are responsible for liver homeostasis and regeneration, researchers say.

“Although hepatocytes appear histologically homogeneous, the liver lobule is actually organized into concentric zones, or rings, in which hepatocytes express different metabolic enzymes across the portal vein-to-central vein axis through which blood flows,” Dr. Hao Zhu of Children’s Medical Center Research Institute at UT Southwestern in Dallas and colleagues explain in Science.

“The identification of the specific liver cell types that regenerate liver tissues over long time periods will affect how we think about chronic liver diseases such as fatty liver and liver cancers,” Dr. Zhu told Reuters Health by email. “We believe that the longest lasting, most regenerative cells are the ones that could accumulate the most mutations and evolve into cirrhotic tissues or malignancies.”

In a series of experiments, Dr. Zhu and colleagues identified genes that were turned on only by specific subsets of hepatocytes, and used these genes as markers to detect the location and function of the different subsets.

They also created 11 mouse models, each of which carried a marker for a specific subset. Working with the new models and three established models, the team observed how the labeled hepatocytes multiplied or disappeared over time, and which were responsible for regeneration after damage.

They found that during homeostasis, zone 1 cells near the portal vein decreased in number over time, as did zone 3 cells near the central vein on the opposite end of the lobule.

However, midlobular zone 2 hepatocytes were largely responsible for repopulation throughout the liver. Those cells were protected from toxic injuries affecting either end of the lobule and thus were well positioned to contribute to regeneration after insults.

“These results challenge the idea that stem cells near the portal or central veins have the highest rates of liver repopulation, but they also support the principle that there are important zonal differences in hepatocyte biology,” the authors state.

Dr. Zhu noted, “If zone 2 cells are the cell of origin of cancer, then we would want to know if those cancers retain some of the original properties of zone 2. If they do not give rise to cancer, then what protects them from doing so? Understanding how these cells adapt and change over time might give us clues as to how to slow the progression of disease.”

“On the therapeutic side of the equation,” he added, “scientists that are trying to generate liver cells to regenerate damaged liver tissues might want to make the cell types that are normally the most regenerative.”

Dr. Michael Karin, Distinguished Professor of Pharmacology and Pathology and Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases at UC San Diego School of Medicine, commented that the study is “a true game-changer in our understanding of liver tissue maintenance and regeneration.”

“That the liver can regenerate itself was already known to the ancient Greeks,” he told Reuters Health by email. “In recent years, different studies have attributed injury-specific generative capacity to subpopulations of zone 1 and zone 3 cells. However, the cell population responsible for maintenance of day-to day-liver mass was unknown until (the authors) showed that this critical function falls on the shoulders of zone 2 cells.”

SOURCE: Science, online February 26, 2021

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