TGF-β-SMAD axis plays an essential role in the regulation of LPC proliferation and performing hepatocyte function in acute liver failure

Background and Aims: Liver progenitor cells (LPCs) performing vital liver function can rescue patients with acute liver failure (ALF) from death. To date, key signaling controlling LPC proliferation and initiating liver functional gene expression remains largely unknown. This study investigates the crosstalk between TGF-β and EGF signaling in LPC proliferation and performing liver functional gene transcription.

Methods: LPC proliferation was examined in DDC-fed mice. Cell type specific spatial transcriptomics was performed on 80 regions of interest selected based on CK7+LPCs, CK8+/18+hepatocytes and CD68+macrophages from 4 ALF patients. Crosstalk between EGF and TGF-β signaling was investigated in LPC line HepaRG cells.

Results: TGF-β inhibits LPC proliferation through impeding G1-S phase transition. Accordingly, LPC proliferation is remarkably increased in DDC-fed SMAD7 transgenic mice, in which TGF-β-induced p-SMAD3 is inhibited, compared to those from wild-type mice. In ALF patients, immunohistochemistry revealed the existence of p-SMAD2 in robustly proliferative LPCs. Spatial transcriptomics demonstrate remarkable activation of both EGF receptor- and TGF-β-dependent genes, which might be driven by EGF and TGF-β from surrounding macrophages. In vitro, EGF prevails TGF-β-dependent proliferative inhibition through impeding SMAD3 binding to the c-MYC promoter. Interestingly, SMADs and c-MYC synergistically promote transcription of vital liver functional genes such as APOA and TF in LPCs.

Conclusions: TGF-β-SMAD signaling physiologically controls LPC proliferation. In ALF, TGF-β-dependent anti-proliferative effect is overtaken by macrophage-derived EGF signaling in activated LPCs. TGF-β-SMAD synergies EGF-c-MYC axis to regulate LPCs to perform hepatocyte function, which is essential for ALF patients’ survival.

Publication History

Article published online:
20 January 2025