Smriti Shubham1, Dhananjay Kumar1, Sheetalnath Rooge1, Jaswinder Sing Maras1, Deepanshu Maheshwari1, Nidhi Nautiyal1, Rekha Kumari1, Adil Bhat1, Guresh Kumar1, Archana Rastogi2, Senthil Kumar3, Viniyendra Pamecha3, Rakhi Maiwall4, Chhagan Bihari2, Anupam Kumar5, Shiv Kumar Sarin6. 1. Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences (ILBS), New Delhi, 110 070, India. 2. Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India. 3. Department of HPB Surgery, Institute of Liver and Biliary Sciences, New Delhi, India. 4. Department of Hepatology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, 110 070, India. 5. Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences (ILBS), New Delhi, 110 070, India. dr.anupamkumar.ilbs@gmail.com. 6. Department of Hepatology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, 110 070, India. sksarin@ilbs.in.
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.
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 ALFpatients. A robust hepatocyte self-replication is lacking in the livers of ACLF patients and is associated with poor survival.
Authors: William Bernal; Anna Hyyrylainen; Amit Gera; Vinod K Audimoolam; Mark J W McPhail; Georg Auzinger; Mohammed Rela; Nigel Heaton; John G O'Grady; Julia Wendon; Roger Williams Journal: J Hepatol Date: 2013-02-22 Impact factor: 25.083
Authors: Y P Sharon Goh; Neil C Henderson; Jose E Heredia; Alex Red Eagle; Justin I Odegaard; Nadja Lehwald; Khoa D Nguyen; Dean Sheppard; Lata Mukundan; Richard M Locksley; Ajay Chawla Journal: Proc Natl Acad Sci U S A Date: 2013-05-28 Impact factor: 11.205
Authors: Luke Boulter; Olivier Govaere; Tom G Bird; Sorina Radulescu; Prakash Ramachandran; Antonella Pellicoro; Rachel A Ridgway; Sang Soo Seo; Bart Spee; Nico Van Rooijen; Owen J Sansom; John P Iredale; Sally Lowell; Tania Roskams; Stuart J Forbes Journal: Nat Med Date: 2012-03-04 Impact factor: 53.440