Z Gastroenterol 2016; 54(12): 1343-1404
DOI: 10.1055/s-0036-1597403
2. Clinical Hepatology
Georg Thieme Verlag KG Stuttgart · New York

Lack of Polarity in liver progenitor cell-derived hepatocytes determines poor clinical outcome of acute-on-chronic liver failure

X Yuan
1   Heidelberg University, Department of Medicine II, Medical Faculty Mannheim, Mannheim, Germany
,
W Gu
2   Shanghai Jiao Tong University, Department of Gastroenterology, RenJi Hospital, School of Medicine, Shanghai, China
,
F Wandrer
3   Hannover Medical School, Department of Gastroenterology, Hepatology and Endoncrinology, Hannover, Germany
,
B Dewidar
1   Heidelberg University, Department of Medicine II, Medical Faculty Mannheim, Mannheim, Germany
,
S Munker
4   University Medical Center, Regensburg, Department of Medicine I, Regensburg, Germany
,
B Haehnel
1   Heidelberg University, Department of Medicine II, Medical Faculty Mannheim, Mannheim, Germany
,
R Liebe
6   Saarland University, Department of Medicine II, Saarland University Medical Center, Homburg, Germany
,
MPA Ebert
1   Heidelberg University, Department of Medicine II, Medical Faculty Mannheim, Mannheim, Germany
,
Q Xia
7   Shanghai Jiao Tong University, Department of Liver Surgery and Liver Transplantation, RenJi Hospital, School of Medicine, Shanghai, China
,
H Bantel
3   Hannover Medical School, Department of Gastroenterology, Hepatology and Endoncrinology, Hannover, Germany
,
S Dooley
1   Heidelberg University, Department of Medicine II, Medical Faculty Mannheim, Mannheim, Germany
,
H Li
7   Shanghai Jiao Tong University, Department of Liver Surgery and Liver Transplantation, RenJi Hospital, School of Medicine, Shanghai, China
,
HL Weng
1   Heidelberg University, Department of Medicine II, Medical Faculty Mannheim, Mannheim, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
19 December 2016 (online)

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Background & Aim: Submassive hepatic necrosis (SMHN) is the defining histological feature of acute-on-chronic liver failure (ACLF). In the areas of SMHN, liver progenitor cells (LPC) critically contribute to liver regeneration. This study investigated the key events that determine LPC-mediated liver regeneration in ACLF following SMHN.

Methods: Liver tissues from 53 ACLF patients (50 receiving liver transplantation (LT) vs. 3 spontaneously recovered) were investigated by immunohistochemistry for Cytokeratin 7 and CD26 to identify LPC/intermediate hepatocyte-like cell (IHLC) and hepatocyte polarity. Transcription factor gene profile was analyzed by microarray. Canaliculi were further examined in collagen sandwich-cultured mouse hepatocytes.

Results: Rapid ductular reaction was observed in all ACLF patients receiving LT even if their clinical duration were 2 days. In these patients, LPC differentiated into IHLC and hepatocytes with time, whereas liver function further deteriorated over time. Notably, LPC-derived hepatocytes did not form canaliculi. In contrast to the patients receiving LT, hepatocytes of recovered ACLF patients displayed intact polarity with formation of canaliculi. Microarray analyses and immunohistochemistry revealed remarkably reduced HNF4α expression in liver tissues from the ACLF patients receiving LT. In contrast, hepatocytes in recovered ACLF patients demonstrated strong HNF4α expression. However, in vitro study showed that disruption of HNF4α expression did not impact hepatocyte polarity.

Conclusion: Recovery from ACLF is associated with formation of canaliculi and strong HNF4αα expression. HNF4α might play a critical role in regulating LPC differentiation towards hepatocytes. Uncovered factors determine polarity with canaliculi formation and function of LPC-derived hepatocytes that decide the clinical outcome of ACLF.