Erythroferrone contributes to iron mobilization for embryo erythropoiesis in iron‐deficient mouse pregnancies

Abstract

Erythroferrone (ERFE) is an erythroblast‐secreted regulator of iron metabolism. The production of ERFE increases during stress erythropoiesis, leading to decreased hepcidin expression and mobilization of iron. Pregnancy requires a substantial increase in iron availability to sustain maternal erythropoietic expansion and fetal development and is commonly affected by iron deficiency. To define the role of ERFE during iron‐replete or iron‐deficient pregnancy, we utilized mouse models expressing a range of ERFE levels: transgenic (TG) mice overexpressing ERFE, wild‐type (WT), and ERFE knockout (KO) mice. We altered maternal iron status using diets with low or standard iron content and performed the analysis at E18.5. Iron deficiency increased maternal ERFE in WT pregnancy. Comparing different maternal genotypes, ERFE TG dams had lower hepcidin relative to their liver iron load but similar hematological parameters to WT dams on either diet. In ERFE KO dams, most hematologic and iron parameters were comparable to WT, but mean corpuscular volume (MCV) was decreased under both iron conditions. Similar to dams, TG embryos had lower hepcidin on both diets, but their hematologic parameters did not differ from those of WT embryos. ERFE KO embryos had lower MCV than WT embryos on both diets. The effect was exacerbated under iron‐deficient conditions where ERFE KO embryos had higher hepcidin, lower Hb and Hct, and lower brain iron concentration compared to WT embryos, indicative of iron restriction. Thus, under iron‐deficient conditions, maternal and embryo ERFE facilitate iron mobilization for embryonic erythropoiesis.

Iron Homeostasis During Pregnancy: Maternal, Placental, and Fetal Regulatory Mechanisms

“…Mechanistic studies in mouse models showed that ERFE knockout mice are fertile (72) and that maternal hepcidin is appropriately suppressed, indicating that ERFE is not the physiological pregnancy hepcidin suppressor. In iron-deficient dams, ERFE deficiency had only very minor effects on maternal erythropoiesis (115). Thus, maternal ERFE may be a useful marker of iron deficiency anemia in pregnancy but does not strongly regulate maternal iron homeostasis.…”

“…In nonanemic human and rodent pregnancies, serum ERFE levels are not significantly affected by pregnancy status (138). However, in mouse models of iron-restricted or iron-deficient pregnancy with ensuing anemia, maternal ERFE levels are significantly elevated (111,115). Elevated maternal ERFE has also been reported in anemic human pregnancies (30).…”

“…Measurement of fetal hepcidin in mice in a healthy pregnancy indicated that fetal hepcidin expression is very low (100,111). However, fetal hepcidin is responsive to stimuli (Figure 1) and can be suppressed by iron deficiency (115) or induced by iron loading (71). Fetal hepcidin is also regulated by ERFE during iron-deficiency anemia, and, in a mouse study, lack of fetal ERFE resulted in increased hepcidin, decreased fetal iron endowment, and diminished fetal erythropoiesis and caused fetal tissue iron deficiency (115).…”

A Decrease in Maternal Iron Levels Is the Predominant Factor Suppressing Hepcidin during Pregnancy in Mice

“…This does not exclude a role for ERFE in pregnancy, as circulating levels are normally very low, with accurate detection using ELISA only possible in conditions of extreme erythroid stimulation, such as in β-thalassemia [ 35 ]. A study showing that pregnant mice lacking ERFE produce smaller erythrocytes—consistent with iron deficiency—supports a role for this hormone in the maintenance of erythroid iron supply during pregnancy [ 36 ]. ERFE suppresses hepcidin by binding to BMP6 and preventing the activation of the SMAD signaling pathway [ 37 ]; however, the level required for suppression likely depends on the amount of BMP6 present.…”

Anemia in Pregnancy With CKD

“… 46 , 54 However, in animal studies of nonanemic pregnancies, ERFE did not appear to play a major role in maternal and fetal iron homeostasis. 55 Finally, in case of maternal iron deficiency anemia, the common homeostatic regulatory mechanisms of iron uptake and transfer to the fetus are engaged and possibly regulated more by fetal than by maternal iron demands. 56 Maternal and fetal hepcidin both decrease further with iron deficiency anemia to promote iron availability and transfer to the fetus.…”