Developmental plasticity of red blood cell homeostasis

Abstract

Most human physiologic set points like body temperature are tightly regulated and show little variation between healthy individuals. Red blood cell (RBC) characteristics such as hematocrit (HCT) and mean cell volume (MCV) are stable within individuals but can vary by 20% from one healthy person to the next. The mechanisms for the majority of this inter-individual variation are unknown and do not appear to involve common genetic variation. Here we show that environmental conditions present during development, namely in utero iron availability, can exert long-term influence on a set point related to the RBC life cycle. In a controlled study of rhesus monkeys and a retrospective study of humans, we use a mathematical model of in vivo RBC population dynamics to show that in utero iron deficiency is associated with a lowered threshold for RBC clearance and turnover. This in utero effect is plastic, persisting at least two years after birth and after the cessation of iron deficiency. Our study reports a rare instance of developmental plasticity in the human hematologic systems and also shows how mathematical modeling can be used to identify cellular mechanisms involved in the adaptive control of homeostatic set points.

Low-Dose Iron Supplementation in Infancy Modestly Increases Infant Iron Status at 9 Mo without Decreasing Growth or Increasing Illness in a Randomized Clinical Trial in Rural China

“…One might speculate that iron supplementation during fetal development altered regulatory processes or set points that facilitated erythropoiesis and repletion of iron stores when supplemental iron was provided above some minimum in infancy. This concept would be consistent with a recent report of developmental plasticity of red blood cell homeostasis during the fetal period: iron availability to the fetus exerted a long-lasting influence on red blood cell clearance and turnover in both monkey and human infants (37). However, our findings require replication before further interpretation, because few infants received even close to the targeted amount of supplemental iron.…”

The Benefits and Risks of Iron Supplementation in Pregnancy and Childhood

“…These findings may explain why certain neurobehavioral effects of early-life iron deficiency appear to be permanent (80,86). Whether early-life iron deficiency affects the regulation of other organ systems, including the production of red blood cells, across the life span is being investigated (51).…”

Hereditary xerocytosis revisited

“…Maturation and senescence of circulating RBCs were evaluated by single‐RBC volume and hemoglobin measurements and a mathematical model of erythrocyte population dynamics to estimate in vivo rates of change in RBC volume and hemoglobin . The proband's circulating RBC population was abnormally homogeneous: coefficients of variation for RBC volume (RDW), hemoglobin mass (HDW), and concentration (CHDW) were low‐normal or below the normal range (data not shown).…”