Angiogenic factors in chronic liver diseases: the effects on hepatic progenitor cells

The biliary tree is a complex network of interconnected ducts, lined by epithelial cells called cholangiocytes, that drains the bile produced by the liver into the duodenum (1). At the periphery of the biliary tree, the interlobular bile ducts continue with the bile ductules, which are entirely constituted by cholangiocytes, may traverse the limiting plate, and are connected with the canal of Hering (2). The latter represents the physical link between the bile canaliculus (formed by the apical membranes of hepatocytes) and the biliary tree, and is thought to be an intrahepatic stem cell niche, harboring the multipotent hepatic stem/progenitor cells (HPCs) (3). To this end, the canal of Hering acts as the centre from which the maturation of both hepatocytes and cholangiocytes arises and proceeds in opposite directions. Indeed, HPCs can give rise to hepatoblasts that are also present as single cells or small aggregates in the canal of Hering and are bipotent cells that can further differentiate into committed progenitors of both the hepatocytic and cholangiocytic lineages. While committed hepatocytic progenitors proceed towards to central vein of the lobule to fully differentiate into mature hepatocytes, cholangiocytic progenitors, also known as “small cholangiocytes”, are thought to move towards the periphery of the biliary tree (4). Recent studies suggest that small cholangiocytes, which can be found up to the bile ductules, are the precursors of large cholangiocytes that, on the other hand, line the interlobular (or larger) bile ducts (5). However, peribiliary glands, which are located in the wall of extrahepatic and large intrahepatic bile ducts, also contain progenitor-like cells and might contribute to or drive the maturation of cholangiocytes (6).