Hepatology 2010 Healthy adult livers have enormous regenerative capacity. This permits recovery of normal tissue-specific functions and mass within weeks of 70% partial hepatectomy

(PH) in humans. Liver regeneration proceeds more rapidly in rodents, which accomplish liver reconstruction within 7 to 10 days after PH.1 Thus, rodents are often used as experimental models to investigate regenerative mechanisms. Such work has consistently demonstrated that striking increases in hepatocyte DNA synthesis occur within the initial 48 hours after PH, followed by smaller (but highly significant) increases in hepatocyte mitoses and eventual recovery of liver mass, leading to consensus that liver regeneration after PH relies largely on increased replication

of mature hepatocytes.2-5 STA-9090 Nevertheless, changes in expression of progenitor markers, such as alpha-fetoprotein (AFP) and Fn14, have long been acknowledged to occur during regeneration.6-9 Severe inhibition of liver regeneration after toxic liver injury was recently reported to occur in mice with targeted disruption of Fn14, a member of the tumor necrosis factor receptor superfamily that promotes the growth of bipotent hepatic progenitors (in other words, oval cells).10 These findings suggest Temsirolimus mw that liver progenitors may have a larger role in regenerating adult livers after PH, and perhaps after other types of acute injury, than previously appreciated. Because mature hepatocyte replication is inhibited in many types of chronic liver injury, it is generally believed that progenitor populations contribute to regeneration of chronically injured livers. However, the mechanisms that mobilize progenitor cells, and that control their fate in damaged livers, are poorly understood.11-13 Recent studies have demonstrated that Hedgehog (Hh), a fetal morphogenic L-gulonolactone oxidase signaling pathway, becomes activated in many types

of chronic liver injury.14 Hh ligands generally promote the growth and viability of progenitor-type cells15-17 and have been shown to function as viability factors for human and rodent liver progenitors, including oval cells. During embryogenesis and cancer metastasis, Hh-pathway activation tends to preferentially expand stromal cell populations by retaining the primitive, migratory phenotype of existing mesenchymal cells and promoting epithelial-to-mesenchymal transitions (EMT) in certain types of immature epithelial cells.18-21 A similar process occurs when the Hh-pathway becomes activated during chronic liver injury because Hh ligands function as growth factors for myofibroblastic liver cells,15, 22 stimulate quiescent hepatic stellate cells to acquire a more myofibroblastic phenotype,23 and induce immature ductular cells to undergo EMT.13 As a result, Hh pathway activation promotes fibrogenic repair responses during chronic liver injury.