Distinct hepatocyte adaptations during gestation and lactation [sheep_SmartSeq3]

The liver undergoes adaptive changes during pregnancy and lactation to meet specific physiological demands, but the precise processes, regulatory mechanisms, and functions remain unclear. Using high-resolution single-cell RNA sequencing (scRNA-seq), we comprehensively analyzed hepatocyte adaptations in mice throughout these periods. Our findings revealed a circular trajectory, termed the “pregnancy clock”, during gestation and non-lactating postpartum phases, reverting to the pre-gestation state after recovery. In contrast, lactation induced a distinct branching pathway, characterized by increased fatty acid synthesis and lipid accumulation. Deletion of Gp130 in the JAK/STAT pathway disrupted gestation transitions, leading to delayed embryonic development, while ACSS2 ablation impaired postpartum lipid metabolism, affecting milk quality and offspring growth. Comparative analysis with sheep demonstrated conserved hepatocyte adaptation pathways despite species-specific genetic regulatory networks. These insights offer potential targets for therapeutic interventions to optimize maternal and fetal health and enhance lactation efficiency, with broad implications for reproductive biology and livestock management. scRNA-seq of sheep hepatocytes during gestation and puerperium days.