Significant progress in identifying cellular sources of ECM in experimental and human liver injury has led to a clearer understanding of fibrogenic cell dynamics during progressive fibrosis. Hepatic stellate cells, the resident perisinusoidal cell type that stores vitamin A, are the major source of ECM during diseases that injure hepatocytes (eg, CCl4 in rodents and viral hepatitis in humans) through their activation into contractile myofibroblasts (1), and a similar transition to myofibroblasts from portal fibroblasts drives the fibrogenic response when biliary cells rather than hepatocytes are injured (2). The liver, with its unique regenerative capacity, has a remarkable ability to resorb scar when either hepatocellular or biliary injury is halted (3, 4). Reduced numbers of fibrogenic cells during fibrosis regression have been ascribed primarily to clearance of myofibroblasts through apoptosis (5), but the question has lingered of whether stellate cells can also revert to a quiescent state and persist as the liver’s normal architecture is restored. In the report by Kisseleva et al.(6) in PNAS, reversion is definitively established in two models of experimental liver injury using complementary genetic lineage tracing methods (Fig. 1). The work by Kisseleva et al.(6) generates mice with activation of stellate cells into myofibroblasts that could be permanently marked through a type I collagen promoter-driven Cre-mediated excision of a stop cassette in a reporter mouse. Because only activated stellate cells express type I collagen within injured liver, this leads to expression of YFP that is restricted to this cell type during fibrosis progression. Consistent with earlier studies, short-term CCl4 administration (a standard hepatocellular toxin that provokes fibrosis) leads to marked activation of almost all stellate cells; however, after 1 mo of CCl4 exposure followed by 4 wk of recovery, substantial reduction of activated stellate cell numbers is apparent (7). At the peak of resolution, 2.6% of activated stellate cells bear markers of apoptosis, whereas YFP is detectable in 56% of cells that also contained vitamin A, indicative of a return to quiescence. Because apoptosis is evanescent, this finding does not mean that only a small fraction of cells undergo cell death, but the findings establish the larger point that a significant number of stellate cells reacquire features of quiescence.

This conclusion is replicated in another model of injury caused by intragastric ethanol administration, indicating that the findings should be generalizable to all forms of hepatocellular injury. Although stellate cells reacquired markers of quiescence during fibrosis resolution, they were not identical to cells that had never activated. Instead, these inactivated stellate cells adopted an intermediate phenotype, with a heightened capacity to reactivate when treated with TGF-β1, a classic fibrogenic signal. Whether these primed stellate cells remain in this state indefinitely or slowly return to full quiescence over a longer interval is not known. Regardless, the data reinforce the known heterogeneity of stellate cells (8, 9), and now, this heterogeneity extends to their variable capacity to quiesce and then reactivate.