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

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Abstract

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.

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Acknowledgements

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).

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Author notes

  1. Smriti Shubham and Dhananjay Kumar equally contributed.

Authors and Affiliations

  1. Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences (ILBS), New Delhi, 110 070, India

    Smriti Shubham, Dhananjay Kumar, Sheetalnath Rooge, Jaswinder Sing Maras, Deepanshu Maheshwari, Nidhi Nautiyal, Rekha Kumari, Adil Bhat, Guresh Kumar & Anupam Kumar

  2. Department of Hepatology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, 110 070, India

    Rakhi Maiwall & Shiv Kumar Sarin

  3. Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India

    Archana Rastogi & Chhagan Bihari

  4. Department of HPB Surgery, Institute of Liver and Biliary Sciences, New Delhi, India

    Senthil Kumar & Viniyendra Pamecha

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  1. Smriti Shubham
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Correspondence to Anupam Kumar or Shiv Kumar Sarin.

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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.

Ethical approval

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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Shubham, S., Kumar, D., Rooge, S. et al. Cellular and functional loss of liver endothelial cells correlates with poor hepatocyte regeneration in acute-on-chronic liver failure. Hepatol Int 13, 777–787 (2019). https://doi.org/10.1007/s12072-019-09983-y

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  • DOI: https://doi.org/10.1007/s12072-019-09983-y

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