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.
