Prometheus revisited: liver homeostasis and repair

nutrients and xenobiotics, as well as a factory and recycling station for a large number of systemic proteins. Its unmatched regenerative capacity was already described in the myth of Prometheus 2500 years ago and extensively studied over the past decades. However, the exact mechanisms enabling maintenance of liver mass during homeostasis and repair remained unclear. Diploid glutamine synthetase (GS)+ pericentral hepatocytes expressing the WNT/β-Catenin target gene Axin2 showed superior proliferative capacity over mostly polyploid hepatocytes in other zones. These GS+/AXIN2+ pericentral hepatocytes were considered liver stem cells as they self-renewed and replaced all hepatocytes along the liver lobule during homeostatic renewal [1]. In contrast, lineage tracing using Lgr5, another WNT/β-Catenin target gene and pericentral hepatocyte marker, did not support increased proliferative capacity and expansion of pericentral hepatocytes into other zones [2, 3]. Likewise, mTERT lineage tracing suggested no zonal dominance of pericentral hepatocytes during liver homeostasis but proposed self-renewing mTERT hepatocytes with increased proliferative capacity as liver stem cells [4]. Moreover, SOX9+ periportal hepatocytes were described as hybrid hepatocytes with liver stem cell properties as they displayed increased regenerative potential in response to injury [5]. The controversy around the elusive liver stem cell arises from the diverse hepatocyte populations that have been proposed to harbor increased regenerative capacity and the conflicting results originating from different lineage tracing experiments under different housing conditions [1-5].