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.

Low iron promotes megakaryocytic commitment of megakaryocytic-erythroid progenitors in humans and mice / Xavier-Ferrucio, Juliana; Scanlon, Vanessa; Li, Xiuqi; Zhang, Ping-Xia; Lozovatsky, Larisa; Ayala-Lopez, Nadia; Tebaldi, Toma; Halene, Stephanie; Cao, Chang; Fleming, Mark D.; Finberg, Karin E.; Krause, Diane S.. - In: BLOOD. - ISSN 0006-4971. - 134:18(2019), pp. 1547-1557. [10.1182/blood.2019002039]

Low iron promotes megakaryocytic commitment of megakaryocytic-erythroid progenitors in humans and mice

Tebaldi, Toma;
2019-01-01

Abstract

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.
2019
18
Xavier-Ferrucio, Juliana; Scanlon, Vanessa; Li, Xiuqi; Zhang, Ping-Xia; Lozovatsky, Larisa; Ayala-Lopez, Nadia; Tebaldi, Toma; Halene, Stephanie; Cao,...espandi
Low iron promotes megakaryocytic commitment of megakaryocytic-erythroid progenitors in humans and mice / Xavier-Ferrucio, Juliana; Scanlon, Vanessa; Li, Xiuqi; Zhang, Ping-Xia; Lozovatsky, Larisa; Ayala-Lopez, Nadia; Tebaldi, Toma; Halene, Stephanie; Cao, Chang; Fleming, Mark D.; Finberg, Karin E.; Krause, Diane S.. - In: BLOOD. - ISSN 0006-4971. - 134:18(2019), pp. 1547-1557. [10.1182/blood.2019002039]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/328055
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