Cellular and functional loss of liver endothelial cells correlates with poor hepatocyte regeneration in acute-on-chronic liver failure
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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.
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.
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.
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.
KeywordsAcute liver failure (ALF) Liver sinusoidal endothelial cells Liver regeneration Hepatocyte proliferation Hepatic progenitor cells (HPCs) Hepatocyte growth factor (HGF) Stromal cell derived factor 1 (SDF1) Liver progenitors
We extend thanks to Department of Pathology for allowing platform for histopathological analysis. We also thank the funding agency Department of Biotechnology, Government of India for financial support (BT/PR8251/MED/31/218/2013).
Compliance with ethical standards
Conflict of interest
Smriti Shubham, Dhananjay Kumar, Sheetalnath Rooge, Jaswinder Sing Maras, Deepanshu Maheshwari, Nidhi Nautiyal, Rekha Kumari, Adil Bhat, Guresh Kumar, Archana Rastogi, Senthil Kumar, Viniyendra Pamecha, Rakhi Maiwall, Chhagan Bihari, Anupam Kumar and Shiv K. Sarin to have no conflict of interest.
All human tissue and blood samples were collected with prior approval from Institutional Research Ethics Committee (F25/5/43/ILBS/2013/IEC/IRB No: 21/6) and informed patient’s consent.
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