Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration

Abstract

SummaryFollowing liver injury, regeneration occurs through self-replication of hepatocytes. In severe liver injury, hepatocyte proliferation is impaired, a feature of human chronic liver disease1,2. It is contested whether other liver cell types can regenerate hepatocytes3–5. Here, we use two independent systems to impair hepatocyte proliferation during liver injury to evaluate the contribution of non-hepatocytes to parenchymal regeneration. Firstly, loss of β1-Integrin in hepatocytes with liver injury triggered a ductular reaction of cholangiocyte origin, and ~25% of hepatocytes being derived from a non-hepatocyte origin. Secondly cholangiocytes were lineage traced with concurrent inhibition of hepatocyte proliferation by β1-Integrin knockdown or p21 over-expression, resulting in the significant emergence of cholangiocyte derived hepatocytes. We describe a model of combined liver injury and inhibition of hepatocyte proliferation that causes physiologically significant levels of regeneration of functional hepatocytes from biliary cells.

Hepatocyte‐Specific β‐Catenin Deletion During Severe Liver Injury Provokes Cholangiocytes to Differentiate Into Hepatocytes

“…To facilitate BEC‐driven repair, we next administered CDE diet to WT2 and KO2 mice for 2 weeks, followed by recovery on normal diet for 2 weeks (Fig. A).…”

“…The role of BECs in mediating LR has remained controversial, as several studies have reported a limited role for BEC differentiation to hepatocytes . Recent studies have demonstrated that widespread hepatocyte senescence, hepatocyte ablation, impaired hepatocyte proliferation, or prolonged exposure to severe liver injury can trigger differentiation of BECs to hepatocytes. Interestingly, a previous study reported ductular reaction and BEC‐to‐hepatocyte differentiation in aged Albumin ‐Cre β‐catenin KO livers, suggesting expression of β‐catenin in hepatocytes is important for long‐term liver health.…”

“…Alternatively, hepatocytes can differentiate into BECs, which can then be incorporated into biliary ductules and may revert back to hepatocytes when injury is withdrawn . There is evidence of BEC‐to‐hepatocyte differentiation in both humans and animal models of liver injury where hepatocyte proliferation is blocked or after near total loss of hepatocytes …”

Limited Regeneration of Adult Salivary Glands after Severe Injury Involves Cellular Plasticity

“…Lineage tracing of duct cells to acinar cells was observed only under conditions of severe cell loss. The ability of lineage-restricted cells to either change phenotype or to generate other cell types to compensate for tissue loss is frequently recognized as a mechanism involved in regeneration (Raven et al, 2017; Thorel et al, 2010). Cellular plasticity is induced in several tissues as part of the normal injury response (Merrell and Stanger, 2016; Tata and Rajagopal, 2016).…”

Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

“…In addition, transplantation of clonogenic LPCs into hepatocyte-senescent murine livers, induced through deletion of the E3 ubiquitin ligase Mdm2, resulted in restoration of the hepatic parenchyma through generation of hepatocytic or biliary epithelia (18). The exact underlying mechanisms of LPC-mediated liver regeneration are not always clear; however, hepatocyte senescence seems to be a definite histological requirement (19).…”