Adv Sci (Weinh). 2026 Jan 29:e17126. doi: 10.1002/advs.202517126. Online ahead of print.
ABSTRACT
Hepatocyte transplantation effectively treats liver failure, yet the regenerative mechanisms driven by engrafted mature hepatocytes remain elusive. Through integrated serial transplantation, lineage tracing, single-cell RNA sequencing (scRNA-seq), and single-cell transposase-accessible chromatin sequencing (scATAC-seq), we show that donor hepatocytes convert into transitional, alpha-fetoprotein-positive reprogrammed hepatocytes (Afp+ rHeps). These cells exhibit controlled proliferation while maintaining unipotent hepatic differentiation potential, enabling fully functional maturation after rapid expansion. Such plasticity is dynamically regulated by AFP expression level-dependent metabolic remodeling through the peroxisome proliferator-activated receptor γ (PPARγ) pathway, which coordinates two functionally distinct subpopulations: Afplow cells sustain proliferation by activating energy metabolism pathways, whereas Afphigh cells adapt to stress by switching to β-oxidation. Additionally, the proliferation of Afp+ rHeps is driven and sustained by tumor necrosis factor-alpha (TNF-α)/activator protein-1 (AP-1) signaling derived from host liver neutrophils. Spatiotemporal analysis further shows that transforming growth factor-beta (TGF-β)-mediated migration precedes PPAR-driven metabolic zonation, ensuring ordered niche adaptation. Together, these findings delineate the molecular basis of liver regeneration mediated by transplanted mature hepatocytes and pinpoint the PPARγ/AFP metabolic axis and TNF-α/AP-1 mitogenic signaling as actionable levers to optimize regenerative therapies based on terminally differentiated hepatocytes.
PMID:41609487 | DOI:10.1002/advs.202517126