TGF-β serves as a critical signaling determinant of liver progenitor cell fate and function

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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 HGF/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 115 regions of interest selected based on CK7 + LPCs, CK8 + /18 + hepatocytes and CD68 + macrophages from 4 ALF patients. Crosstalk between HGF/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 HGF/EGF receptor- and TGF-β-dependent genes, which might be driven by HGF/EGF and TGF-β from surrounding hepatic stellate cells and macrophages. In vitro, either EGF or HGF promotes LPC proliferation at the presence of TGF-β. Although the anti-proliferative effect of TGF-β was compromised in LPCs, the robust TGF-β-SMAD signaling played additional essential effects in ALF, including upregulating HNF4α expression in LPCs. Conclusions: TGF-β-SMAD signaling physiologically controls LPC proliferation. In ALF, TGF-β-dependent anti-proliferative effect is overtaken by HGF/EGF signaling in activated LPCs. TGF-β-SMAD synergies HGF/EGF-c-MYC axis to regulate LPCs to perform hepatocyte function, which is essential for ALF patients' survival. Publication History Article published online: 04 September 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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