期刊
BLOOD
卷 134, 期 18, 页码 1547-1557出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2019002039
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资金
- Orkin laboratory (Boston Children's Hospital, Boston, MA)
- Connecticut Regenerative Medicine Research Fund
- Li Ka Shing Foundation
- National Blood Foundation Early-Career Scientific Research Grant
- Gruber Science Fellowship
- Burroughs Wellcome Career Award for Medical Scientists
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK094934, DK114031, DK086267]
- National Institutes of Health, National Heart Lung and Blood Institute [2T32HL00797416]
- NIDDK [1U54DK106857]
The mechanisms underlying thrombocytosis in patients with iron deficiency anemia remain unknown. Here, we present findings that support the hypothesis that low iron biases the commitment of megakaryocytic (Mk)-erythroid progenitors (MEPs) toward the Mk lineage in both human and mouse. In MEPs of transmembrane serine protease 6 knockout (Tmprss6(-/-)) mice, which exhibit iron deficiency anemia and thrombocytosis, we observed a Mk bias, decreased labile iron, and decreased proliferation relative to wild-type (WT) MEPs. Bone marrow transplantation assays suggest that systemic iron deficiency, rather than a local role for Tmprss6(-/-) in hematopoietic cells, contributes to the MEP lineage commitment bias observed in Tmprss6(-/-) mice. Nontransgenic mice with acquired iron deficiency anemia also show thrombocytosis and Mk-biased MEPs. Gene expression analysis reveals that messenger RNAs encoding genes involved in metabolic, vascular endothelial growth factor, and extracellular signal-regulated kinase (ERK) pathways are enriched in Tmprss6(-/-) vs WT MEPs. Corroborating our findings from the murine models of iron deficiency anemia, primary human MEPs exhibit decreased proliferation and Mk-biased commitment after knockdown of transferrin receptor 2, a putative iron sensor. Signal transduction analyses reveal that both human and murine MEP have lower levels of phospho-ERK1/2 in iron-deficient conditions compared with controls. These data are consistent with a model in which low iron in the marrow environment affects MEP metabolism, attenuates ERK signaling, slows proliferation, and biases MEPs toward Mk lineage commitment.
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