• Liver Stem Cells Identified

Liver Stem Cells Identified

Scientists have identified stem cells in the liver that give rise to functional liver cells. The work solves a long-standing mystery about the origin of new cells in the liver, which must constantly be replenished as cells die, even in a healthy organ.

“We’ve solved a very old problem,” senior author Roel Nusse, said in a press release from the Howard Hughes Medical Institute. “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.” Nusse et al reported their findings online August 5, 2015 in Nature.

The liver comprises mostly hepatocytes, which store vitamins and minerals, remove toxins, and regulate fats and sugars in the bloodstream. As these cells die off, they are replaced by healthy new hepatocytes. The source of those new cells had never been identified, Nusse said.

Some scientists have speculated that mature hepatocytes maintain their populations by dividing. But Nusse says the mature cells have become so specialized to carry out the work of the liver, they have likely lost the ability to divide. Nusse studied a cell population in livers of mice that maintain homeostasis when they are positioned in a specialized zone.

Stem cells labeled in red and green around the central vein of the liver. The stem cells give rise to progeny (green) that expand across the lobule. This image shows the result of lineage-tracing in a mouse for 1 year. Credit: Nusse Lab, HHMI at Stanford University

Stem cells labeled in red and green around the central vein of the liver. The stem cells give rise to progeny (green) that expand across the lobule. This image shows the result of lineage-tracing in a mouse for 1 year. Credit: Nusse Lab, HHMI at Stanford University

Hepatocytes in the pericentral region immediately adjacent to the central vein replicate slightly faster than other hepatocytes in normal conditions, and are the only hepatocyte population that expresses genes activated by the Wnt signaling pathway.

In lineage-tracing experiments with a Wnt-responsive gene (Axin2) in mice, Nusse and colleagues identified a population of proliferating and self-renewing cells adjacent to the central vein in the liver lobule (see figure). These pericentral cells remained close to the central vein and were normally replaced by other hepatocytes. They expressed the early liver progenitor marker Tbx3 and were diploid—setting them apart from mature hepatocytes, which are mostly polyploid.

The descendants of the pericentral cells differentiated into Tbx3-negative, polyploid hepatocytes, and could replace all hepatocytes along the liver lobule during homeostatic renewal. Nusse and colleagues found that adjacent central vein endothelial cells provided Wnt signals that maintain the pericentral cells.

Over time, these cells gave rise to descendants outside the pericentral zone that can replenish up to 40% of the liver’s mass under normal conditions.

In a News and Views article in the same issue, Kenneth Zaret explains that nutrient-rich blood from the intestines travels along the portal vein, arriving in the portal zone of the liver, where bile ducts and the hepatic artery also reside. The blood then travels through sinuses in the liver mass, is exposed to hepatocytes for metabolite and toxin exchange, and collects in the central vein. The portal zone must therefore contend with greater toxic insults than the central zone. Periportal hepatocytes respond to most forms of liver damage, and can also contribute to homeostatic cell renewal.

Zaret says that the findings of Nusse and colleagues lead to the question of how pericentral hepatocytes differ from other hepatocytes, and whether the difference depends on their proximity to the central vein.

Zaret believes the discovery that pericentral hepatocytes, along with other hepatocytes, contribute to liver homeostasis opens up many avenues for study. For instance, the relative contribution of each of these cell types to homeostatic regeneration is not known. The role of pericentral hepatocytes in regeneration following non-periportal forms of liver damage also remains to be determined. Manipulating the Wnt pathway in vivo might provide insights along these lines.

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