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

Area of Science:

• Hematology
• Molecular Biology
• Cell Biology

Background:

• The mechanisms linking iron deficiency anemia (IDA) to thrombocytosis are not fully understood.
• Iron's role in hematopoietic stem cell differentiation, particularly megakaryopoiesis, requires further elucidation.

Purpose of the Study:

• To investigate the hypothesis that low iron influences megakaryocytic (Mk)-erythroid progenitor (MEP) lineage commitment.
• To explore the molecular pathways affected by iron deficiency in MEPs.

Main Methods:

• Utilized transmembrane serine protease 6 knockout (Tmprss6-/-) mice exhibiting IDA and thrombocytosis.
• Performed bone marrow transplantation assays to assess systemic vs. local effects of iron deficiency.
• Analyzed gene expression and signal transduction pathways (ERK signaling) in murine and human MEPs.
• Investigated human MEPs following transferrin receptor 2 knockdown.

Main Results:

• Tmprss6-/- mice and non-transgenic mice with acquired IDA showed thrombocytosis and a Mk-biased MEP lineage commitment.
• MEPs from iron-deficient models exhibited decreased labile iron and proliferation.
• Gene expression analysis revealed enrichment of metabolic, VEGF, and ERK pathway genes in iron-deficient MEPs.
• Human MEPs with reduced transferrin receptor 2 showed decreased proliferation and Mk bias, with lower phospho-ERK1/2 levels.

Conclusions:

• Systemic iron deficiency, not local Tmprss6 deficiency, drives the MEP lineage bias.
• Low iron in the bone marrow microenvironment attenuates ERK signaling, reduces MEP proliferation, and promotes Mk lineage commitment.
• These findings provide a mechanistic link between iron deficiency anemia and thrombocytosis.