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Liver Regeneration Revealed: Hepatocytes Beget Hepatocytes

Prometheus Karl-Ludwig Poggemann FlickrThe liver is one of the tissues with the highest capacity to regenerate in the body. Indeed, the Greek myth of Prometheus is an advertisement for this extraordinary ability, as the Titan’s liver was eaten daily by an eagle only to regrow each night for the cycle to repeat itself. And knowing exactly how this quick turnover occurs in the liver might help patients with such diseases as cirrhosis, hepatitis, and cancer.

The regenerating liver is center stage in a modern story about how science similarly reinvents and readjusts itself, with a paper out in an early September issue of Cell Stem Cell from the lab of Ben Stanger, who is affiliated with the departments of Medicine (division of Gastroenterology) and Cell and Developmental Biology, as well as the Penn Institute for Regenerative Medicine  and the Abramson Family Cancer Research Institute. In fact, Markus Grompe from the Oregon Health & Science University in  Portland, wrote in a Cell Stem Cell commentary on the Stanger paper that, “facultative liver stem cells have long been thought to be an important source of new hepatocytes during chronic liver injury. This longstanding paradigm is being challenged by two papers discussed herein.”

The Stanger paper challenges the idea – prevalent for several decades - that the liver uses stem cells (called atypical ductal cells) for regeneration following injury. But, this notion was based largely on test tube studies and transplants, in which results have been conflicting. Science often has to rely on such “model” experimental systems to study a problem, but this always leaves open the question of whether the findings obtained from such methods reflect the actual situation inside the body.

The Stanger lab used new tools to mark and track the origin and contribution of various cell populations to map liver regeneration. What made the study different from prior work is that the tracing was conducted in live mice following injury, using tools whose tracking of cell specificity could be carefully measured.

The Penn team came to a contrary finding to prevailing stem-cell-based models of regeneration. The team looked at many liver cell types before and after injury, asking what cell type turns into what cell type They found that virtually all new hepatocytes (the most common kind of liver cell) come from pre-existing hepatocytes, not stem cells. Biliary and the atypical ductal cells of the liver did not give rise to hepatocytes.

The liver is constantly exposed to toxins, viruses, and needs to repair, and it’s the hepatocytes, the workhorse cell of the liver that does the detoxification. So what do oval cells do then? Perhaps they become new liver ducal cells after an injury, surmises Stanger, “maybe they make more of the liver’s plumbing ducts after an injury.”

Stanger characterizes this study as a “negative result, really,” but one that challenges the current model of liver regeneration. “If stem cells play a minor or minimal role in liver regeneration inside the body, then it doesn’t make a great deal of sense to keep looking for them. This study emphasizes therefore that the focus should be on the hepatocyte replication itself. How does the liver ‘know,’ when it’s time to make new hepatocytes, and how does the organ maintain its structure during regeneration?”

These are very old questions and now they are more pressing than ever.

Image credit: Prometheus/Karl-Ludwig Poggemann via Flickr Creative Commons



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