During pregnancy, iron needs to increase substantially to support fetoplacental development and maternal adaptation to pregnancy. To meet these iron requirements, both dietary iron absorption and the mobilization of iron from stores increase, a mechanism that is in large part dependent on the iron-regulatory hormone hepcidin. In healthy human pregnancies, maternal hepcidin concentrations are suppressed in the second and third trimesters, thereby facilitating an increased supply of iron into the circulation. The mechanism of maternal hepcidin suppression in pregnancy is unknown, but hepcidin regulation by the known stimuli (i.e., iron, erythropoietic activity, and inflammation) appears to be preserved during pregnancy. Inappropriately increased maternal hepcidin during pregnancy can compromise the iron availability for placental transfer and impair the efficacy of iron supplementation. The role of fetal hepcidin in the regulation of placental iron transfer still remains to be characterized. This review summarizes the current understanding and addresses the gaps in knowledge about gestational changes in hematologic and iron variables and regulatory aspects of maternal, fetal, and placental iron homeostasis.

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Aging is associated with diminished muscle mass, reductions in muscle stem cell functions, and increased muscle fibrosis. The immune system, especially macrophages, can have important roles in modulating muscle growth and regeneration, suggesting that the immune system may also have significant influences on muscle aging. Moreover, the immune system experiences changes in function during senescence, suggesting that regulatory interaction between muscle cells and the immune system may also change during aging. In this study, we performed bone marrow transplantations between age-mismatched donor and recipient mice to test the influence of the age of the immune system on muscle aging. Transplantation of young bone marrow cells into old recipients prevented sarcopenia and prevented age-related change in muscle fiber phenotype. Transplantation of old bone marrow cells into young animals reduced satellite cell numbers and promoted satellite cells to switch toward a fibrogenic phenotype. We also demonstrated that conditioned media from young, but not old, bone marrow cells promoted myoblast proliferation in vitro, and we found that factors released by young bone marrow cells were more supportive of myotube differentiation in vitro. Together, our results demonstrate that aging of bone marrow cells promotes the age-related reduction of satellite cell number and function and contributes to sarcopenia.-Wang, Y., Wehling-Henricks, M., Welc, S. S., Fisher, A. L., Zuo, Q., Tidball, J. G. Aging of the immune system causes reductions in muscle stem cell populations, promotes their shift to a fibrogenic phenotype, and modulates sarcopenia.

Iron disorders are associated with adverse pregnancy outcomes, yet iron homeostatic mechanisms during pregnancy are poorly understood. In humans and rodents, the iron-regulatory hormone hepcidin is profoundly decreased in pregnant mothers, which is thought to ensure adequate iron availability for transfer across placenta. However, the fetal liver also produces hepcidin, which may regulate fetal iron endowment by controlling placental iron export. To determine the relative contribution of maternal vs embryo hepcidin to the control of embryo iron endowment in iron-sufficient or iron-overloaded mice, we generated combinations of mothers and embryos that had or lacked hepcidin. We found that maternal, but not embryonic hepcidin determined embryo and placental iron endowment in a healthy pregnancy. We further determined that inflammation can counteract pregnancy-dependent suppression of maternal hepcidin. To establish how essential maternal hepcidin suppression is for embryo iron homeostasis, we mimicked the range of maternal hepcidin activity by administering a hepcidin peptide mimetic to pregnant mice. This also allowed us to determine the effect of isolated maternal hepcidin excess on pregnancy, in the absence of other confounding effects of inflammation. Higher doses of hepcidin agonist caused maternal iron restriction and anemia, lower placenta and embryo weight, embryo anemia, and increased embryo mortality. Low agonist doses did not cause maternal anemia but still adversely affected the embryo, causing anemia, tissue iron deficiency including in the brain, and decreased weight. Our studies demonstrate that suppression of maternal hepcidin during pregnancy is essential for maternal and embryo iron homeostasis and health.

Iron homeostasis is tightly regulated to balance the iron requirement for erythropoiesis and other vital cellular functions, while preventing cellular injury from iron excess. The liver hormone hepcidin is the master regulator of systemic iron balance by controlling the degradation and function of the sole known mammalian iron exporter ferroportin. Liver hepcidin expression is coordinately regulated by several signals that indicate the need for more or less iron, including plasma and tissue iron levels, inflammation, and erythropoietic drive. Most of these signals regulate hepcidin expression by modulating the activity of the bone morphogenetic protein (BMP)‐SMAD pathway, which controls hepcidin transcription. Genetic disorders of iron overload and iron deficiency have identified several hepatocyte membrane proteins that play a critical role in mediating the BMP‐SMAD and hepcidin regulatory response to iron. However, the precise molecular mechanisms by which serum and tissue iron levels are sensed to regulate BMP ligand production and promote the physical and/or functional interaction of these proteins to modulate SMAD signaling and hepcidin expression remain uncertain. This critical commentary will focus on the current understanding and key unanswered questions regarding how the liver senses iron levels to regulate BMP‐SMAD signaling and thereby hepcidin expression to control systemic iron homeostasis.