Researchers from the Children’s Medical Center Research Institute at UT Southwestern (CRI; TX, USA) have identified the group of cells responsible for liver maintenance and regeneration and their location in the liver. This study, published in Science, answers some fundamental questions about liver maintenance, liver damage and liver cancer.

While the regenerative power of the liver has been known for centuries, there has been recent debate about whether only a subset of hepatocytes or stem cells across the lobule is responsible for the production of new cells.

Previous work in this area was hindered by a lack of markers to distinguish the functions of the various types of hepatocytes. However, researchers at the CRI’s Zhu lab were able to overcome this challenge, comparing the genes that mark hepatocytes throughout the liver to identify those that were only turned on by specific subsets of hepatocytes. These genes were then used as markers to distinguish the identities and functions of different hepatocyte subsets.

This led to the creation of 11 new mouse strains, each carrying a marker for a specific group of hepatocytes. The team observed how the labelled cells multiplied or diminished over time using these new mouse strains, alongside three previously established strains. This enabled them to discern which of these cells were responsible for liver regeneration after damage, directly comparing each subset’s role in liver maintenance and regeneration.

The researchers discovered a trend in the role of these cells according to which part of the liver they occupied. Cells in zone 2 gave rise to new hepatocytes that populated all three zones of the lobules, while cells from zones 1 and 3 disappeared, suggesting that it’s the role of a common set of hepatocytes within a specific region of the liver that are responsible for liver regeneration, rather than a rare population of stem cells.

Further, upon exposing mice to chemicals that mimicked common forms of liver damage, the team also demonstrated that cells in zone 2 were better at evading death, regenerating hepatocytes and sustaining 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,” explained lead author Hao Zhu (CRI). “However, more investigation is needed to understand the different cell types in the human liver.”

Further study into the genes important for growth and regeneration led to the discovery of the IGFBP2-mTOR-CCND1 axis, a pathway that was more active in zone 2 than in zones 1 and 3. Disruption of this pathway in mice meant that cells in zone 2 were no longer able to generate new hepatocytes, therefore establishing this pathway as the regenerative mechanism used by zone 2 cells.

Zhu commented: “The identification of zone 2 hepatocytes as a regenerative population answers some fundamental questions about liver biology and could have important implications for liver disease. In addition, the tools we created to study different types of hepatocytes can be used to examine how different cells respond to liver damage or to genetic changes that cause liver cancer.”

Link: https://www.regmednet.com/cells-responsible-for-liver-regeneration-identified/