Hepato-biliary stem cells: facts and fancies

The canals of Hering and stem cells At the close of the 20 century, a decades long questions was finally settled: both rodent and human livers had facultative hepato-biliary stem cells. The stem cell niche in which these cells’ activities were identified was the canal of Hering (CoH) [1] – the link between hepatocyte canaliculi and the biliary tree. This structure had been functionally demonstrated by Ewald Hering in 1857, but its anatomic structure was merely inferred, but not visualized. Hering’s suggested that the link was located at the limiting plate, where hepatic parenchyma encountered portal tract stroma. His initial drawings depicted that hypothesis. The first direct imagings of the CoH were via electron microscopy, which confirmed that the CoH, as Hering intuited, was comprised of hepatocytes on one side and the smallest cholangiocytes on the other, but these high powered, ultrastructural views could not really explore the canal’s tissue level anatomic structure. Immunohistochemistry (for biliary keratins) and serial sectioning to create a three dimensional analysis of CoH in human livers solved the question [2]. Human CoH were not as small as thought and not restricted to the limiting plate; rather, they were delicate structures that extended across the limiting plate, into the periportal parenchymal regions, as much as a third of the way toward the central vein (but no further). It was from these structures that new hepatocytes were seen to be arising in the setting of severe acute injury (e.g. acetaminophen toxicity) [2] and in chronic liver diseases of all kinds (reviewed in [3]). These findings led to significant paradigm shifts. For hepato-biliary regeneration, settling of the argument as to whether there actually were liver stem cells potentiated explosive creativity in exploring their physiologic behavior and theraperutic potential. For pathology, the ubiquitous, but poorly understood “ductular reactions” (DR) – seen in all severe acute injuries and in all advanced stage chronic liver disease – were now understood to be tissue activations of the hepatobiliary stem cell niche [3].