Iron availability for erythropoiesis is controlled by the iron-regulatory hormone hepcidin. Increased erythropoiesis negatively regulates hepcidin synthesis by erythroferrone (ERFE), a hormone produced by erythroid precursors in response to erythropoietin (EPO). The mechanisms coordinating erythropoietic activity with iron homeostasis in erythrocytosis with low EPO are not well defined as exemplified by dominantly inherited (heterozygous) gain-of-function mutation of human EPO receptor (mtHEPOR) with low EPO characterized by postnatal erythrocytosis. We previously created a mouse model of this mtHEPOR that develops fetal erythrocytosis with a transient perinatal amelioration of erythrocytosis and its reappearance at 3–6 weeks of age. Prenatally and perinatally, mtHEPOR heterozygous and homozygous mice (differing in erythrocytosis severity) had increased Erfe transcripts, reduced hepcidin, and iron deficiency. Epo was transiently normal in the prenatal life; then decreased at postnatal day 7, and remained reduced in adulthood. Postnatally, hepcidin increased in mtHEPOR heterozygotes and homozygotes, accompanied by low Erfe induction and iron accumulation. With aging, the old, especially mtHEPOR homozygotes had a decline of erythropoiesis, myeloid expansion, and local bone marrow inflammatory stress. In addition, mtHEPOR erythrocytes had a reduced lifespan. This, together with reduced iron demand for erythropoiesis, due to its age-related attenuation, likely contributes to increased iron deposition in the aged mtHEPOR mice. In conclusion, the erythroid drive-mediated inhibition of hepcidin production in mtHEPOR mice in the prenatal/perinatal period is postnatally abrogated by increasing iron stores promoting hepcidin synthesis. The differences observed in studied characteristics between mtHEPOR heterozygotes and homozygotes suggest dose-dependent alterations of downstream EPOR stimulation.

中文翻译：

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人功能获得性红细胞生成素受体小鼠铁代谢和红细胞生成的发育变化

红细胞生成的铁可用性受铁调节激素铁调素控制。增加的红细胞生成负调节红细胞生成素 (ERFE) 的铁调素合成，ERFE 是一种由红细胞前体响应促红细胞生成素 (EPO) 产生的激素。在低 EPO 的红细胞增多症中，协调红细胞生成活性与铁稳态的机制尚未明确定义，例如以出生后红细胞增多症为特征的低 EPO的人 EPO 受体 ( mtHEPOR ) 的显性遗传（杂合）功能获得性突变为例。我们之前创建了这种mtHEPOR的小鼠模型，该模型发展为胎儿红细胞增多症，红细胞增多症在围产期短暂改善，并在 3-6 周龄时再次出现。产前和围产期，mtHEPOR杂合子和纯合子小鼠（红细胞增多症严重程度不同）的Erfe转录物增加，铁调素减少和缺铁。产前Epo暂时正常；然后在出生后第 7 天下降，并在成年期保持下降。出生后， mtHEPOR杂合子和纯合子中的铁调素增加，伴随着低 Erfe 诱导和铁积累。随着年龄的增长，老年人，尤其是mtHEPOR纯合子的红细胞生成减少，骨髓扩张和局部骨髓炎症应激。此外，mtHEPOR红细胞的寿命缩短。这与红细胞生成对铁的需求减少（由于其与年龄相关的衰减）可能导致老年mtHEPOR小鼠的铁沉积增加。总之，红系驱动介导的mtHEPOR小鼠在产前/围产期对铁调素产生的抑制在出生后通过增加促进铁调素合成的铁储存而被消除。在mtHEPOR杂合子和纯合子之间的研究特征中观察到的差异表明下游 EPOR 刺激的剂量依赖性改变。