In the setting of chronic liver injury in humans, epidermal growth factor (EGF) and EGF receptor (EGFR) are up-regulated and have been proposed to have vital roles in both liver regeneration and development of hepatocellular carcinoma (HCC). Chronic liver injury also leads to hepatic stellate cell (HSC) differentiation and a novel subpopulation of HSCs which express CD133 and exhibit properties of progenitor cells has been described in rats. The carbon tetrachloride (CCl 4)-induced mouse model has been historically relied upon to study liver injury and regeneration. We exposed mice to CCl 4 to assess whether EGF and CD133+ HSCs are up-regulated in chronically injured liver.
Multiple well-differentiated HCCs were found in all livers after 15 weeks of CCl 4 treatment. Notably, HCCs developed within the setting of fibrosis and not cirrhosis. CD133 was dramatically up-regulated after CCl 4 treatment, and increased expression of desmin and glial fibrillary acidic protein, representative markers of HSCs, was also observed. EGF expression significantly decreased, contrary to observations in humans, whereas the expression of amphiregulin, another EGFR ligand, was significantly increased.