The Neural Crest as the First Production Site of the Erythroid Growth Factor Erythropoietin

Abstract

While the neural crest is considered the fourth germ layer that originates a variety of tissues during mammalian development, we recently discovered that some neural crest cells and neuroepithelial cells play a unique role in secreting a vital hematopoietic hormone, erythropoietin (EPO), in mouse embryos. EPO production by the neural crest is transient in mid-stage embryos but essential for the first erythropoiesis in the yolk sac and for sufficient oxygen supply in the whole embryo growing in utero . The site of EPO production shifts from the neural crest to the liver in late embryonic stages, followed by interstitial fibroblasts of the kidneys in adults. Interestingly, the transition of EPO production sites synchronizes with the transition of erythropoietic sites during mouse development from the yolk sac and the fetal liver to the bone marrow. EPO produced by the neural crest and the neuroepithelium is first stored around the production sites and delivered to the yolk sac as an endocrine hormone for erythropoiesis after heartbeat activation. The fact that EPO is produced by some human cell lines derived from neuroblastoma, which mainly originates from the neural crest, provides evidence that the neural crest secretes EPO for primitive erythropoiesis not only in mouse but also in human embryos. Here, we introduce and discuss recent progress in studies on the mechanism of EPO production by the neural crest and its roles in erythropoietic development and in the fate of EPO-producing neural crest cells.

The Many Facets of Erythropoietin Physiologic and Metabolic Response

“…During mammalian development, observations of EPO production in mice suggest that EPO is first expressed transiently in neural crest cells during mid-gestation to stimulate yolk sac primitive erythropoiesis for oxygen transport in mid-stage embryos (Malik et al, 2013;Suzuki et al, 2013;Hirano and Suzuki, 2019). As development progresses, the liver becomes the site of EPO production and definitive erythropoiesis FIGURE 1 | Pleiotropic effects of erythropoietin.…”

The Role of PI3K/AKT and MAPK Signaling Pathways in Erythropoietin Signalization

“…Low-level secretion of EPO is sufficient for classical steady-state erythropoiesis but its production is increased during hypoxia and anemia. The first site of EPO production is considered to be neural crest cells and neuroepithelial cells that transiently secrete EPO during the early stages of embryogenesis [ 2 ]. In the late embryogenesis, EPO distribution is shifted to the fetal liver [ 3 ], whereas adult EPO production resides in the specialized kidney interstitial fibroblasts called pericytes [ 4 ].…”

Alteration of the DNA Methylation Signature of Renal Erythropoietin-Producing Cells Governs the Sensitivity to Drugs Targeting the Hypoxia-Response Pathway in Kidney Disease Progression

“…While the etiologies of CKD are diverse, ranging from lifestyle-related diseases to autoimmune disorders, CKD progression is commonly accompanied by kidney fibrosis, in which myofibroblasts emerge and proliferate in the renal tubular interstitium (Quaggin and Kapus, 2011). Because kidneys are the major organs producing erythroid growth factor erythropoietin (EPO) in adult mammals (Suzuki, 2015; Hirano and Suzuki, 2019), erythropoiesis is often impaired in CKD patients (Nangaku and Eckardt, 2006). The liver supportively produces EPO under anemic conditions, but hepatic EPO production cannot adequately compensate for renal EPO production in renal anemia patients.…”