Attenuation of liver fibrosis development by angiotensin 2 receptor blocker 1- treatment augments hepatocyte differentiation of hepatic progenitor cells

Recent research has elucidated mechanisms and potentials of hepatic progenitor cells (HPC) on regeneration of diseased liver. It is commonly known that hepatic stellate cells (HSC) play important roles as niche component cells of HPC, and that HPC expands along with HSC activation and liver fibrosis development. However, less is known about whether liver fibrosis development affects HPC-mediated regeneration. We have reported anti-fibrotic effect of angiotensin 2 receptor blocker 1 (ARB) on diseased liver by inhibition of HSC activation. Our current study was performed to elucidate interactions between HSC and HPC-mediated liver regeneration using ARB on DDC-induced mouse liver model. DDC-treatment augmented liver injury with fibrosis development and HPC expansion. ARB-treatment attenuated α-SMA-positive activated HSC with increased hepatocyte (HC) differentiation of HPC, which may result in gain of liver/body weight ratio. Our in vitro experiments showed that ARB treatment did not alter capacity for HPC differentiation. In contrast, co-culture of HPC and human HSC line (LX-2) augmented biliary epithelial cell (BEC) differentiation of HPC but attenuated efficiency for hepatocyte differentiation. Treatment with angiotensin 2 enhanced this polarity of HPC differentiation towards BEC, which was blocked by ARB. These results indicated that HSC augments HPC differentiation fates towards BEC. Anti-fibrosis treatment may also be beneficial on efficient HPC-mediated liver regeneration via preferential differentiation of HPC towards HC.