Surrounding the liver’s central vein are stem cells (labeled red and green) that give rise to progeny (green) that expand across the lobule. This image is from a mouse that was lineage-traced for one year. [Nusse Lab, HHMI at Stanford]
Surrounding the liver’s central vein are stem cells (labeled red and green) that give rise to progeny (green) that expand across the lobule. This image is from a mouse that was lineage-traced for one year. [Nusse Lab, HHMI at Stanford]

The liver’s ability to renew itself in response to injury is not just the stuff of legend (thanks Prometheus), it is also the object of intense research. Less appreciated and understood—both culturally and scientifically—is the liver’s ability to maintain itself day by day, replacing uninjured cells that die off naturally. While the liver’s capacity for routine maintenance has never inspired myth making, it has inspired a search for the origin of new cells in the healthy liver.

These new cells, report Howard Hughes Medical Institute (HHMI) scientists, arise from a fairly obscure subset of stem cells. Before these stem cells were identified, some scientists entertained the idea that mature hepatocytes might maintain their populations by dividing. This idea, however, didn’t impress the HHMI scientists, who were led by Roel Nusse, M.D., Ph.D., an HHMI investigator at Stanford University.

“Differentiated hepatocytes have amplified their chromosomes,” Dr. Nusse explained. That is, the cells have more than the usual two copies of every chromosome. “This enables the cells to make more proteins, but it really compromises their ability to divide.”

Dr. Nusse and colleagues decided to focus on a family of proteins called Wnts, which are key regulators of stem cell fate. To find and follow stem cells in a variety of tissues, they developed mice in which cells that respond to the Wnt signal are labeled with a fluorescent protein.

Ultimately, the researchers carried out lineage tracing using the Wnt-responsive gene Axin2 in mice, and they identified a population of proliferating and self-renewing cells adjacent to the central vein in the liver lobule. They described this work in an article (“Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver”) that appeared August 5 in Nature.

“These pericentral cells express the early liver progenitor marker Tbx3, are diploid, and thereby differ from mature hepatocytes, which are mostly polyploidy,” wrote the authors. “The descendants of pericentral cells differentiate into Tbx3-negative, polyploid hepatocytes, and can replace all hepatocytes along the liver lobule during homeostatic renewal. Adjacent central vein endothelial cells provide Wnt signals that maintain the pericentral cells, thereby constituting the niche.”

Essentially, the scientists noticed that the cells they were tracking divided rapidly, steadily replenishing their own population. This was possible because unlike mature hepatocytes, the labeled cells had only two copies of each chromosome.

By following the descendents of the stem cells for up to a year, the scientists discovered that these had changed, taking on the specialized features and amplified genomes of mature hepatocytes. “This fits the definition of stem cells,” noted Dr. Nusse.

As expected, the liver stem cells required Wnt signals to maintain their stem cell identity. Nusse's team discovered that endothelial cells lining the central vein, the blood vessel around which the stem cells were clustered, released Wnt molecules into the tissue. Stem cells that migrated out of reach of that signal quickly lost their ability to divide into new stem cells and began to develop into mature hepatocytes. Nusse says this is consistent with how stem cells are known to behave in other tissues.

“We've solved a very old problem,” asserted Dr. Nusse. “We've shown that like other tissues that need to replace lost cells, the liver has stem cells that both proliferate and give rise to mature cells, even in the absence of injury or disease.”

The lab is now investigating how the newly identified stem cells might contribute to regeneration of liver tissue after injury. It will also be important to explore whether liver cancers tend to originate in these replicating cells, as opposed to more mature hepatocytes, Dr. Nusse advised.

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