Fig. 2.

Zonal regeneration principles.

(A) Zone 1 hepatocytes show plasticity and can undergo reprogramming to turn on genes normally expressed in BECs, while losing expression of hepatocyte genes. Sometimes hepatocytes can fully transdifferentiate into BECs. BECs are also reported to give rise to hepatocytes when existing hepatocytes in all zones are senescent. (B) Zone 2 and 3 hepatocytes also have plasticity, but different from zone 1. After injury to zone 3, zone 1 and 2 hepatocytes proliferate to repair the damage, and zone 2 hepatocytes are reported to undergo transient fetal reprogramming to adopt a zone 3 fate in response to WNT signalling from zone 3 endothelial cells. Whereas persistent WNT signalling drives zone 3 metabolism, uncontrolled WNT signalling promotes liver tumours, highlighting tumour risk from Zone 3 hepatocytes. (C) However, porto-central upregulation of WNT signalling (indicated by Axin2 upregulation; as well as upregulation of many other factors not shown here⁷⁴) also drives a wave of hepatocyte proliferation following partial hepatectomy. Additionally, hepatocytes are observed to downregulate metabolism as they proliferate, enabling a division of labour for some hepatocytes to proliferate as others maintain metabolic function. DEN, diethylnitrosamine; BECs, biliary epithelial cells; PHx, partial hepatectomy.