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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.

SUBMITTER: Golub MS

PROVIDER: S-EPMC4086753 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Developmental plasticity of red blood cell homeostasis.

Golub Mari S MS Hogrefe Casey E CE Malka Roy R Higgins John M JM

American journal of hematology 20140303 5

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 developmen ...[more]

PMID: 24415575

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Project description:Asymptomatic malaria infections may affect red blood cell (RBC) homeostasis. Reports indicate a role for chronic hemolysis and splenomegaly, however, the underlying processes are incompletely understood. New hematology analysers provide parameters for a more comprehensive analysis of RBC hemostasis. Complete blood counts were analysed in subjects from all age groups (n = 1118) living in a malaria hyperendemic area and cytokines and iron biomarkers were also measured. Subjects were divided into age groups (<2 years, 2-4, 5-14 and ≥15 years old) and clinical categories (smear-negative healthy subjects, asymptomatic malaria and clinical malaria). We found that hemoglobin levels were similar in smear-negative healthy children and asymptomatic malaria children but significantly lower in clinical malaria with a maximum difference of 2.2 g/dl in children <2 years decreasing to 0.1 g/dl in those aged ≥15 years. Delta-He, presenting different hemoglobinization of reticulocytes and RBC, levels were lower in asymptomatic and clinial malaria, indicating a recent effect of malaria on erythropoiesis. Reticulocyte counts and reticulocyte production index (RPI), indicating the erythropoietic capacity of the bone marrow, were higher in young children with malaria compared to smear-negative subjects. A negative correlation between reticulocyte counts and Hb levels was found in asymptomatic malaria (ρ = -0.32, p<0.001) unlike in clinical malaria (ρ = -0.008, p = 0.92). Free-Hb levels, indicating hemolysis, were only higher in clinical malaria. Phagocytozing monocytes, indicating erythophagocytosis, were highest in clinical malaria, followed by asymptomatic malaria and smear-negative subjects. Circulating cytokines and iron biomarkers (hepcidin, ferritin) showed similar patterns. Pro/anti-inflammatory (IL-6/IL-10) ratio was higher in clinical than asymptomatic malaria. Cytokine production capacity of ex-vivo whole blood stimulation with LPS was lower in children with asymptomatic malaria compared to smear-negative healthy children. Bone marrow response can compensate the increased red blood cell loss in asymptomatic malaria, unlike in clinical malaria, possibly because of limited level and length of inflammation. Trial registration: Prospective diagnostic study: ClinicalTrials.gov identifier: NCT02669823. Explorative cross-sectional field study: ClinicalTrials.gov identifier: NCT03176719.

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Developmental plasticity of red blood cell homeostasis.

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Developmental plasticity of red blood cell homeostasis.

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