Z Gastroenterol 2025; 63(01): e1-e2
DOI: 10.1055/s-0044-1800988
Abstracts │ GASL
Lecture Session I
BASIC HEPATOLOGY (FIBROGENESIS, NPC) 14/02/2025, 01.10pm – 01.55pm, Lecture Hall

Extracellular matrix protein 1 (ECM1) balances liver regeneration by interfering with HGF/c-Met-ERK-MYC and TGF-β-SMAD signaling pathways

Ye Yao
1   Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University; Mannheim, Germany
,
Yujia Li
1   Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University; Mannheim, Germany
,
Chenjun Huang
2   Medical Faculty Mannheim, Heidelberg University;Shanghai University of Traditional Chinese Medicine, Shanghai, China.
,
Seddik Hammad
1   Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University; Mannheim, Germany
,
Laura Danielczyk
1   Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University; Mannheim, Germany
,
Chunfang Gao
3   Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
,
Matthias Ebert
4   Medical Faculty Mannheim, Heidelberg University-Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany;DKFZ-Hector Cancer Institute at the University Medical Center, Mannheim, Germany
,
Honglei Weng
1   Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University; Mannheim, Germany
,
Steven Dooley
1   Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University; Mannheim, Germany
,
Sai Wang
5   Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University; Mannheim, Germany
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Objective: Extracellular matrix protein 1 (ECM1) is crucial for liver homeostasis and negatively correlates with chronic liver disease (CLD) progression. However, its role in acute liver injury and regeneration (LR) remains unclear. This study investigates ECM1's impact on LR and its underlying mechanisms.

Design: Ecm1-tdTomato mice were administered adeno-associated virus 8 (AAV8)-ECM1 seven days before 70% partial hepatectomy (PHx). Hepatic gene expression was analyzed with RNA sequencing. Functional assays were done with hepatocytes, mouse liver tissue and patient samples.

Results: ECM1 is downregulated during LR after PHx. Interference with ECM1 downregulation by AAV8-ECM1 delays proliferation and liver mass gain at days 2 and 4, but catches up by day 8, as indicated by the liver-to-body weight ratio and immunostaining of PCNA and Ki67. Mechanistically, in early-stages of LR (days 0–4), downregulation of ECM1 is required for efficient HGF/c-MET/ERK/MYC signaling to mediate cell cycle progression, including CyclinA2, B1, B2, and Birc5 expression. In the late stage (days 4–8), overexpression of ECM1 inhibits latent TGF-β activation, therefore interfering with TGF-β-induced cell cycle kinase inhibitors p15, p16, p18, and p19, required for regeneration termination, which finally restores the liver mass. Additionally, Myc overexpression in hepatocytes rescues ECM1 mediated proliferation inhibition. In liver tissue of patients, ECM1-positive hepatocytes display reduced nuclear Myc expression.

Conclusion: ECM1 regulates liver regeneration by modulating HGF/c-MET/ERK/MYC and TGF-β/SMAD pathways. We hypothesize that for patients requiring liver regeneration, ECM1 downregulation benefits hepatocyte proliferation and liver function restoration. However, its inhibitory effect on TGF-β signaling should also be considered.



Publication History

Article published online:
20 January 2025

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