Abstract
When massive hepatic necrosis–associated (MHN-associated) acute liver failure (ALF) occurs following severe damage, liver progenitor cells (LPCs) exit quiescence and enter differentiation programs during which they acquire hepatocyte-like functions. How LPCs maintain quiescence under physiological conditions and orchestrate activation following MHN remains largely unknown. We elucidate an essential role of TGF-β in regulating LPC quiescence and activation. Spatial transcriptomics and single-cell sequencing revealed that LPCs receive multiple signals, particularly TGF-β, HGF, and EGF, from surrounding hepatic stellate cells and macrophages in patients and zebrafish with MHN-induced ALF. Physiologically, TGF-β inhibits LPC proliferation by blocking G1-to-S phase transition, an effect reversed by Smad7 overexpression in a murine injury model. We observed extensive LPC proliferation in patients with ALF despite strong TGF-β/phosphorylated SMAD signaling. Immunostaining revealed concurrent activation of HGF/MET, EGF/EGFR, and downstream STAT3/ERK pathways in LPCs. In vitro, HGF or EGF overcame TGF-β–mediated growth arrest and promoted LPC proliferation. Beyond acting as a mitogen, HGF additionally induced hepatocyte gene programs (e.g., Hnf4a, Hnf1a) in LPCs. Strikingly, TGF-β signaling was required for HGF-dependent hepatocyte gene induction, indicating a dual role in restraining LPC proliferation and promoting functional maturation. These findings position TGF-β as a context-dependent determinant of LPC activation and lineage specification during ALF.
Authors
Chenhao Tong, Tao Lin, Han Wang, Luyao Jiang, Xiaodong Yuan, Wenwu Luo, Minghan Zhou, Carolina De La Torre, Hui Liu, Chen Shao, Seddik Hammad, Hui Gao, Jiarong Xie, Lei Xu, Roman Liebe, Zuguang Gu, Matthias P. Ebert, Huiguo Ding, Steven Dooley, Hong-Lei Weng
Figure 2
Cell-cell communications between LPCs, macrophages, and HSCs in ALF.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)