Hypoxia Signaling in the Cell Type-Specific Regulation of Erythropoietin Production Throughout Mammalian Development

To maintain the oxygen supply to peripheral organs, the production of erythropoietin (EPO), an essential growth factor for red blood cells, is controlled in a hypoxia-inducible manner in mammals. The developmentally earliest site of EPO production, which is necessary for primitive erythropoiesis in the yolk sac and bloodstream, is found in a subset of neural crest and neuroepithelial cells during mid-stage embryonic development. These neural EPO-producing (NEP) cells maintain their immaturity and EPO-producing ability in their hypoxic microenvironment, which is inherent in developing embryos. After oxygenation of the fetus by the establishment of the circulatory system and EPO-driven erythropoiesis, the site of EPO production shifts to hepatocytes of the fetal liver, where erythropoiesis also occurs. In adult mammals, a specific fibroblastic cell fraction in the renal interstitium, known as renal EPO-producing (REP) cells, secretes the majority of EPO to support bone marrow erythropoiesis. Hypoxia-inducible transcription factors (HIFs) are involved in EPO production across NEP cells, hepatocytes, and REP cells, whereas the regulatory mechanisms are distinct for each cell type. This review summarizes the molecular mechanisms of EPO gene regulation throughout all life stages and discusses the associations of HIF signaling in EPO production with other stimuli, including inflammation and metabolism.