Conversion of Transplanted Mature Hepatocytes into Afp ⁺ Reprogrammed Cells for Liver Regeneration After Injury

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: Afp ^low cells sustain proliferation by activating energy metabolism pathways, whereas Afp ^high 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.