Cellular and functional loss of liver endothelial cells correlates with poor hepatocyte regeneration in acute-on-chronic liver failure.

Background and Aim: Acute hepatic insult triggers regeneration. If acute-on-chronic liver failure (ACLF) patients have a poorer regenerative response than acute liver failure (ALF) patients, and if so, the mechanisms underlying this, are not well understood.
Methods: We investigated the status of hepatocyte proliferation, hepatic progenitor cell (HPC) mediated regeneration, non-parenchymal cells (through immunohistochemistery), cytokines and growth factors (cytokine bead array) in liver and peripheral blood of ACLF (n = 29) and ALF (n = 17) patients. Liver endothelial cells, mesenchymal cells and Kupffer cells were isolated from explant livers and analysis of regenerative factors was done by qRT-PCR.
Results: Unlike ALF, the ACLF livers showed decreased hepatocyte proliferation (p < 0.001) and profound ductular-reaction with increased CK19 + hepatocytes (p < 0.0001). However, only decrease in Ki67+ hepatocytes was associated with 28 day mortality in ACLF (p < 0.001; HR = 0.78; 95% CI 0.69-0.88). In both groups, increase in plasma hepatocyte growth factor (HGF) (OR = 21.87 p = 0.002;), macrophage colony stimulating factor (MCSF) (OR = 21.73; p = 0.002) and stromal derived factor (SDF1)(OR = 10.2; p = 0.001) were associated with hepatocyte proliferation and decreased (> fivefolds) levels were associated with poor hepatocyte regeneration in ACLF patients. ACLF livers showed decrease in endothelial cells (p < 0.01) and expression of regenerative angiocrine factors C-X-C chemokine receptor type 7 (CXCR7), Inhibitor of DNA Binding 1(IDI) and HGF compared to ALF. In co-culture, while ALF liver mesenchymal stromal cells (LMSCs) induced the expression of CXCR7, IDI and HGF in human umbilical cord endothelial cells (HUVECs), the ACLF LMSCs were defective and showed decreased production of SDF-1, HGF and MCSF compared to ALF.
Conclusions: Decrease in hepatic endothelial cells and their regenerative angiocrine functions indicated by defective CXCR7-ID1 dependent HGF expression underlie the poor hepatocyte proliferation in ACLF compared to ALF patients. A robust hepatocyte self-replication is lacking in the livers of ACLF patients and is associated with poor survival.