Cholangiocyte regeneration and liver repair are impaired in HDC−/− mice following 70% partial hepatectomy via dysregulated Notch signaling
Authors: Francis Heather , Hargrove Laura , Meng Fanyin , Kennedy  , DeMorrow Sharon , Alpini Gianfranco 
Published: November 2023

BackgroundThe liver is the only organ capable of tissue regeneration after injury and only 25% of the remaining liver tissue is required for the liver to regenerate and function normally. At day 3 following 70% partial hepatectomy (PH), cholangiocytes (the cells lining the biliary epithelium) proliferate and contribute to the regrowth of the liver. Along the length of biliary epithelium there are distinct subpopulations of cholangiocytes, including small (<8 μM) and large (>13 μM) cholangiocytes, which differentially respond to liver injury with changes in proliferative and apoptotic responses. Notch signaling is a crucial factor of cell fate during development and liver regeneration and Notch 1 is upregulated following PH. Histamine (HA), whose synthesis is regulated by the enzyme histidine decarboxylase (HDC), is a trophic, growth‐promoting factor during liver injury/repair that induces its effects via H1–H4 histamine receptors (HRs). We have previously shown that (i) treatment with endogenous HA or a specific H1 histamine receptor (HR) agonist increases normal cholangiocyte proliferation and accelerates liver regeneration following 70% PH and (ii) in HDC knockout mice (HDC−/−) there is decreased biliary proliferation. The aim of the current study was to demonstrate that HA contributes to the repair and regeneration of the liver following 70% PH via Notch signaling.MethodsWild‐type (WT) and HDC−/− mice were subjected to sham or 70% PH and sacrificed at 1 and 3 days before serum, snap liver and liver tissues were collected. To evaluate pathological changes in small and large intrahepatic bile duct mass (IBDM), we performed immunhistochemistry for CK‐19 (bile duct marker). Small and large cholangiocyte proliferation was measured by Ki67 by immunohistochemistry and semi‐quantitative analysis in liver sections. The expression of PCNA, Notch 1 and Notch 2 was measured in total liver by real‐time PCR. Histamine serum release was measured by EIA.ResultsAt day 1 following PH, large IBDM is increased in both WT and HDC−/− mice; however large IBDM is significantly less in HDC−/− mice compared to WT. After 3 days following PH, there is a significant increase in small, but not large IBDM in WT that is ablated in HDC−/− mice. Large IBDM is not changed in PH HDC−/− mice at day 3 compared to day 1. The expression of Notch 1 and 2 increased in PH WT mice at day 1 and 3. In PH HDC−/− mice, the expression of Notch 1 was significantly higher than PH WT mice at day 1, whereas Notch 2 expression decreased in PH HDC−/− mice at day 3. Histamine serum concentration was increased in WT mice subjected to PH at day 1 and 3 compared to sham surgery and in PH HDC−/− mice the levels of histamine were significantly decreased.ConclusionThere is a differential response in proliferation of small and large cholangiocytes in WT mice subjected 70% PH where large IBDM increases first and is followed by small cholangiocyte regeneration. Knockdown of HDC alters the response of small and large cholangiocytes by inducing changes in Notch signaling and thereby inhibiting the complete regrowth of the liver. Targeting histamine may offer a novel strategy for post‐transplantation recipients.Support or Funding InformationVA Career Development Award