Z Gastroenterol 2020; 58(01): e3
DOI: 10.1055/s-0039-3402106
Lectures Session II Clinical Hepatology, Surgery, LTX: Friday, February 14, 2020, 3:25 pm – 4:10 pm, Lecture Hall P1
Georg Thieme Verlag KG Stuttgart · New York

Activin-driven fate determination is pivotal for liver progenitor cells to take over hepatocytic function in in ACLF

T Lin
1   Medical Faculty Mannheim, Heidelberg University, Department of Medicine II, Section Molecular Hepatology, MANNHEIM, Germany
,
S Wang
1   Medical Faculty Mannheim, Heidelberg University, Department of Medicine II, Section Molecular Hepatology, MANNHEIM, Germany
2   You'an Hospital, Affiliated with Capital Medical University, Department of Gastroenterology and Hepatology, Beijing, China
,
R Feng
1   Medical Faculty Mannheim, Heidelberg University, Department of Medicine II, Section Molecular Hepatology, MANNHEIM, Germany
,
C Shao
3   Beijing You'an Hospital, Affiliated with Capital Medical University, Department of Pathology, Beijing, China
,
X Yuan
1   Medical Faculty Mannheim, Heidelberg University, Department of Medicine II, Section Molecular Hepatology, MANNHEIM, Germany
,
F Wandrer
4   Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
,
H Bantel
4   Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
,
A Marx
5   Medical Faculty Mannheim, Heidelberg University, Institute of Pathology, Mannheim, Germany
,
MPA Ebert
1   Medical Faculty Mannheim, Heidelberg University, Department of Medicine II, Section Molecular Hepatology, MANNHEIM, Germany
,
H Ding
2   You'an Hospital, Affiliated with Capital Medical University, Department of Gastroenterology and Hepatology, Beijing, China
,
S Dooley
1   Medical Faculty Mannheim, Heidelberg University, Department of Medicine II, Section Molecular Hepatology, MANNHEIM, Germany
,
H Weng
1   Medical Faculty Mannheim, Heidelberg University, Department of Medicine II, Section Molecular Hepatology, MANNHEIM, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2020 (online)

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Background & Aim:

Liver progenitor cell (LPC) differentiation into mature hepatocytes determines survival and recovery of patients with acute-on-chronic liver failure (ACLF), who suffer from massive hepatic necrosis. Interestingly, even in irreversible ACLF, LPCs differentiate towards hepatocytes. However, these LPC-derived hepatocytes do not provide sufficient hepatocytic function, as required for systemic homeostasis. This study demonstrates a crucial role of Activin-dependent lineage-determining transcription factor HNF4a in the maintenance of key hepatocyte function.

Methods:

This study enrolled 28 ACLF patients (20 receiving liver transplantation and 8 spontaneously recovered). Expression of transcription factors in liver tissues was measured by immunohistochemistry. Murine LPCs were used to investigate the regulatory mechanisms underlying HNF4a expression.

Results: In vitro, LPCs express HNF4a and key hepatic functional genes/proteins, e.g. albumin and coagulation factor V (f5). Knockdown of HNF4a remarkably reduces expression of these genes/proteins. ChIP assays confirm that HNF4a controls albumin and f5 gene expression by binding to their promoters. Activin, but not TGF-β, induces HNF4a expression in LPCs. Co-IP analyses further indicate that Activin-mediated HNF4a expression requires formation of two transcription factor complexes, TRIM33-SMAD2/3 and FOXH1-SMAD2/3/4. Knocking down any components interferes with HNF4a and target gene expression. Interestingly, Activin administration or depletion of HNF4a does not alter the epigenetic phenotype of LPCs, e.g. H3K4me3, H3K27me3 and H3K27ac expression, indicating that the Activin-HNF4a axis does not induce cell reprogramming. Consistent with the in vitro findings, 8 recovered ACLF patients display robust expression of p-Smad2, TRIM33, FoxH1 and HNF4a in LPC nuclei, whereas irreversible ACLF patients lost multiple or all transcription factors. We found a negative association between HNF4a expression and MELD scores, that is, all recovered patients displayed both high levels of HNF4a and low MELD scores. In contrast, none of the irreversible ACLF patients demonstrated robust HNF4a expression in LPCs. In ACLF patients, expression of H3K4me3, H3K27me3 and H3K27ac was not relevant toHNF4a expression.

Conclusions:

These results highlight a key mechanism of Activin signal-driven lineage determination for avoiding liver failure. Targeting the Activin-HNF4a axis might provide a novel approach in ACLF treatment.