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

Area of Science:

• Hepatology
• Cellular Biology
• Regenerative Medicine

Background:

• Hepatocyte transplantation is a promising treatment for liver failure.
• The precise mechanisms by which transplanted mature hepatocytes regenerate the liver are not fully understood.

Purpose of the Study:

• To elucidate the regenerative mechanisms of engrafted mature hepatocytes in liver failure treatment.
• To identify key molecular pathways and cellular interactions driving hepatocyte regeneration.

Main Methods:

• Integrated serial transplantation, lineage tracing, single-cell RNA sequencing (scRNA-seq), and single-cell transposase-accessible chromatin sequencing (scATAC-seq).
• Analysis of hepatocyte conversion, proliferation, differentiation potential, and signaling pathways.
• Spatiotemporal analysis of cell migration and niche adaptation.

Main Results:

• Donor hepatocytes transform into transitional, alpha-fetoprotein-positive reprogrammed hepatocytes (Afp+ rHeps) with controlled proliferation and unipotent differentiation potential.
• Hepatocyte plasticity is regulated by the peroxisome proliferator-activated receptor γ (PPARγ) pathway, coordinating Afp-low (proliferation, energy metabolism) and Afp-high (stress adaptation, β-oxidation) subpopulations.
• Proliferation of Afp+ rHeps is driven by tumor necrosis factor-alpha (TNF-α)/activator protein-1 (AP-1) signaling from host liver neutrophils.
• Transforming growth factor-beta (TGF-β)-mediated migration precedes PPAR-driven metabolic zonation, ensuring ordered niche adaptation.

Conclusions:

• Transplanted mature hepatocytes regenerate the liver through a process involving reprogramming, controlled proliferation, and dynamic metabolic and signaling regulation.
• The PPARγ/AFP metabolic axis and TNF-α/AP-1 signaling are critical regulators of hepatocyte regeneration.
• These findings identify actionable targets for optimizing regenerative therapies using terminally differentiated hepatocytes.