The conundrum of the pericentral hepatic niche: WNT/β-Catenin signaling, metabolic zonation and many open questions.

WNT/β-Catenin signaling promotes stemness, proliferation and cell fate decisions in various tissue stem cell compartments, which maintain organs with a high turnover of cells (e.g. skin, stomach and gut). Thus, the β-Catenin target genes AXIN2 and LGR5 are widely considered as tissue stem cell markers. In contrast, AXIN2 and LGR5 are expressed in pericentral hepatocytes, which do not show overt proliferation during liver homeostasis. Given the low hepatocyte turnover, the liver does not require constant high rates of proliferation, whereas WNT/β-Catenin signaling is critical for metabolic zonation. Yet, WNT/β-Catenin pathway upregulation, including AXIN2 and LGR5 induction in hepatocytes throughout the liver, enables hepatocyte regeneration in response to various injuries. In this mini review, we discuss the role of WNT/β-Catenin in controlling metabolic zonation and the conundrum around pericentral hepatocytes that have been proposed as liver stem cells.