Chromatin dynamics and regulatory drivers of hypoplastic hepatic progenitor cells in partial hepatectomy model

The remarkable plasticity of hepatocytes underlies diverse roles in distinct patterns of liver injury. Specifically, hepatocyte-derived progenitor cells play dominant roles in driving the regenerative response during chronic liver injury. However, the potential for hepatocytes to transdifferentiate into progenitor-like cells following partial hepatectomy (PHx) remains debated. In this study, we generate single-nucleus Assay for Transposase Accessible Chromatin using sequencing (snATAC-seq) data from mice subjected to the 2/3 PHx, aiming to characterize the dynamics of hepatocyte chromatin accessibility and the existence of hepatic progenitor cells. Our findings reveal that PHx induces dynamic changes in hepatocyte chromatin accessibility, giving rise to distinct hepatocyte subtypes balancing metabolic functions and proliferative activities. Notably, a subset of hepatocytes displays enhanced accessibility of progenitor cell-associated genes (e.g., Sox9 and Tnfrsf12a), along with increased accessibility to reprogramming-related genes (RRGs). By integrating with transcriptome data, we identify a hepatocyte population exhibiting progenitor-like traits. However, these progenitor-like cells show limited contribution to liver regeneration in the PHx model. Mechanistically, our results suggest that disrupted critical crosstalks (e.g., Pdgfa-Pdgfra signaling) with immune cells are attributed to impaired hepatic progenitor cells activation. Moreover, concurrent activation of growth signals in hepatocytes and other non-parenchymal cells (NPCs) suppresses the activation of progenitor cells. PHx-induced chromatin dynamics reveal transient progenitor-like hepatocytes with limited regeneration contribution, hindered by impaired immune crosstalk and growth signals.