The liver is the only solid organ that uses regenerative mechanisms to ensure that the liver-to-bodyweight ratio is always at 100% of what is required for body homeostasis. When the liver is injured beyond its ability to regenerate itself, a liver transplant is needed and used to treat conditions such as liver cancer, cirrhotic liver disease, acute liver failure, and genetic liver disorders. The amazing regenerative power of the liver is no secret. However, the cells and mechanisms behind it remained a mystery, until now. Researchers from the Children’s Medical Center Research Institute at UT Southwestern (CRI) have pinpointed the cells responsible for liver maintenance and regeneration while also identifying where they reside.

Their findings, “Liver homeostasis is maintained by midlobular zone 2 hepatocytes,” were published in the journal Science, and can provide insights into liver diseases, maintenance, and damage. The research was led by Hao Zhu, MD, an associate professor at CRI.

“Previous efforts to identify the most-regenerative hepatocytes have not definitively resolved fundamental questions about whether regenerative activity is spatially restricted within particular zones or whether rare or common subsets of hepatocytes are responsible,” the researchers wrote.

Researchers in the Zhu lab compared the genes that mark hepatocytes throughout the liver. The researchers identified genes that were only turned on by specific subsets of hepatocytes, and then used these genes as markers to distinguish the identities and functions of different hepatocyte subsets. The researchers created 11 new mouse strains, each of which carries a marker for a specific subset of hepatocytes. They observed how the labeled cells multiplied or disappeared over time, and which were responsible for liver regeneration after damage.

Liver lobule structure, identifying the three zones. [UT Southwestern Medical Center]
They discovered that cells in zone 2 gave rise to new hepatocytes that populated all three zones of liver lobules while cells from zones 1 and 3 disappeared. These findings suggested there is a common set of mature hepatocytes within a specific region of the liver that regularly divide to make new hepatocytes throughout the liver. The researchers used mice to model common forms of liver damage, showing that cells in zone 2 were able to regenerate hepatocytes, and sustain liver function.

“In humans, cells in zones 1 and 3 are most often harmed by alcohol, acetaminophen, and viral hepatitis. So it makes sense that cells in zone 2, which are sheltered from toxic injuries affecting either end of the lobule, would be in a prime position to regenerate the liver. However, more investigation is needed to understand the different cell types in the human liver,” said Zhu.

“This study reconciles findings from multiple groups and offers a more unified view of hepatocyte repopulation. The identification of zone 2 hepatocytes as a regenerative population has far-reaching implications for the cellular basis of chronic disease pathogenesis, cancer development, and regenerative medicine strategies,” concluded the researchers.