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 and mean cell volume 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 2 years after birth and after the cessation of iron deficiency. Our study reports a rare instance of developmental plasticity in the human hematologic system and also shows how mathematical modeling can be used to identify cellular mechanisms involved in the adaptive control of homeostatic set points.

Figure 1. Red blood cell (RBC) characteristics

Complete blood counts (CBCs) were performed between birth and two years of age for monkeys whose mothers received iron deprived (ID) or iron sufficient (IS) diets during pregnancy. Data are shown as mean ± SEM. N=10/group. Mean RBC volume (MCV); mean RBC hemoglobin content (MCH); mean RBC hemoglobin concentration (MCHC). P values for group comparisons from RMANOVA are shown in the figure. There was a significant effect of age for all endpoints (p=0.02–0.01), with no significant age*group interactions for any endpoint.

Figure 2. Dynamics of RBC maturation and clearance as modeled in rhesus monkeys

Reticulocytes (top right of panel A) are released from the bone marrow into the circulation. The volume (x-axis) and hemoglobin content (y-axis) of individual reticulocytes decline rapidly at first and then more slowly, with rapid rates quantified by model parameters β_v (panel C) and β_h (D) and the slower rate by parameter α (panel D). The magnitude of variation in rates across the population of cells is quantified by model parameters D_v (panel E) and D_h (panel F), and the clearance threshold by v_c (panel G). All parameters are dimensionless. See “Methods for Mathematical Modeling of RBC Populations” for detail. Boxplots show the extent and diversity for each estimated parameter. See the caption for Figure S2 for additional detail on boxplots.

Figure 3. In utero iron deficiency is associated with persistent delay in RBC clearance in two-year-old rhesus monkeys

Panels A and B show the single-RBC volume and hemoglobin distributions for an IS (panel A) and an ID (panel B) animal. A gray plane divides the populations at 90% of the MCV and MCH. In the IS RBC population, 21% of the circulating RBCs are located between the plane and origin at steady state, as compared to 27% in the ID animal. Panel C shows that this difference between the ID (5 animals) and IS (5 animals) groups is significant with a p-value of 0.008 (one-sided rank sum test), supporting the conclusion that in utero iron deprivation causes a long-lasting delay in RBC clearance with more low volume and hemoglobin cells in the ID animals. The “MCHC” lines in A and B show the mean single-RBC hemoglobin concentration. Contour lines in A and B enclose 90%, 75%, 50%, and 12.5% of cells.

Figure 4. In utero iron deficiency is associated with persistent delay in RBC clearance in two-year-old humans

Panels A and B show the single-RBC volume and hemoglobin distributions for a typical IS (panel A) and a typical ID (panel B) child. A gray plane divides the populations al 90% of the MCV and MCH. For the IS child, 19% of the circulating RBCs are located between the plane and origin at steady state, as compared to 25% for the ID child. Panel C shows that this difference between the 19 ID children and 28 IS children is significant with a p-value of 0.012 (one-sided rank sum test), supporting the model prediction that in utero iron deprivation causes a long-lasting delay in RBC clearance with more low volume and hemoglobin cells in the ID children. The “MCHC” lines in A and B show the mean single-RBC hemoglobin concentration. Contour lines in A and B enclose 90%. 75%, 50%, and 12.5% of cells.