On the origin of the liver

Abstract

While it has been well established that the fetal liver originates from foregut endoderm, the identity of the mechanisms that maintain liver mass under both basal and injury conditions remains controversial. Dramatically different models have been proposed based on the experimental design employed. In this issue of the JCI, Malato and colleagues report their elegant new model for genetic lineage tracing of mature mouse hepatocytes using an adenoassociated virus-driven Cre recombinase. They show convincingly that maintenance of liver mass during normal turnover or in response to mild injury is achieved by mature hepatocytes, rather than cholangiocytes or specialized progenitor cells, as has been suggested by others.

Figure 1. Comparison of 2 models of liver cell homeostasis using pulse labeling.

In this hypothetical example, Sox9-expressing cells (pink) and hepatocytes (yellow) are permanently marked, as are all their progeny. (A) In the model proposed by Furuyama et al. (17), after labeling, Sox9-expressing cells differentiate into both cholangiocytes and hepatocytes, ultimately populating the entire lobule. This requires streaming of the Sox9-derived hepatocytes from zone 1 to zone 3. (B) The data presented by Malato and colleagues in this issue of the JCI (1) support a distinct model in which, under most conditions, hepatocytes are derived from other hepatocytes, without any contribution from nonhepatocytes. In some forms of injury, a small percentage of hepatocytes are derived from a nonhepatocyte cell population, perhaps from Sox9-expressing stem cells.