Biological maturation drives the hepatic-to-renal switch in erythropoietin production at birth

BACKGROUND: Erythropoietin (EPO) is essential for erythropoiesis, with production shifting from the foetal liver to the kidney after birth. This hepatic-to-renal transition is a hallmark of neonatal adaptation, but the relative contribution of oxygen exposure versus intrinsic developmental processes remains unclear. METHODS: We studied plasma EPO isoform profiles in 89 neonates (developmental age 29-56 weeks; chronological age 1-92 days). Isoforms were classified as hepatic-like or renal-like based on isoelectric focusing patterns. Profiles were correlated with developmental and chronological age to assess the influence of oxygen exposure versus maturation. In parallel, human induced pluripotent stem cells (hiPSCs) were differentiated into liver organoids and cultured under hypoxic or normoxic conditions. Transcriptome and EPO mRNA expression were measured throughout differentiation to evaluate developmental and oxygen-dependent regulation. FINDINGS: Neonatal EPO profiles shifted progressively from hepatic-like to renal-like with increasing developmental age. This transition was independent of time spent in atmospheric oxygen; preterm infants retained hepatic-like profiles for weeks after birth despite continuous oxygen exposure. In cellulo, immature hepatocytes expressed EPO robustly under hypoxia, but expression declined sharply as hepatocyte maturation advanced and was absent at later stages, regardless of oxygen tension. Maintaining the immature state of hepatic cells may be critical for responsiveness to hypoxia and for EPO production. INTERPRETATION: These findings indicate that intrinsic hepatic maturation, rather than oxygenation, governs the silencing of hepatic-derived EPO after birth. Clarifying this process could support novel therapeutic strategies aimed at reactivating foetal-like hepatic EPO production to treat anaemia, particularly in preterm infants and in conditions associated with insufficient renal EPO production, such as chronic kidney disease. FUNDING: This study was mainly supported by the Région des Pays de la Loire, The French National Agency for Research (ANR), the Fonds Européen de Développement Régional Bourgogne Franche Comté, the Marie Skłodowska-Curie action, and the Fondation Génavie.