Increased Iron Uptake by Splenic Hematopoietic Stem Cells Promotes TET2-Dependent Erythroid Regeneration

Authors

Yu-Jung Tseng
Yuki Kageyama
Rebecca L Murdaugh
Ayumi Kitano
Jong Hwan Kim
Kevin A Hoegenauer
Jonathan Tiessen
Mackenzie H Smith
Hidetaka Uryu
Koichi Takahashi
James F Martin
Md Abul Hassan Samee
Daisuke Nakada

Publication Date

1-15-2024

Journal

Nature Communications

Abstract

Hematopoietic stem cells (HSCs) are capable of regenerating the blood system, but the instructive cues that direct HSCs to regenerate particular lineages lost to the injury remain elusive. Here, we show that iron is increasingly taken up by HSCs during anemia and induces erythroid gene expression and regeneration in a Tet2-dependent manner. Lineage tracing of HSCs reveals that HSCs respond to hemolytic anemia by increasing erythroid output. The number of HSCs in the spleen, but not bone marrow, increases upon anemia and these HSCs exhibit enhanced proliferation, erythroid differentiation, iron uptake, and TET2 protein expression. Increased iron in HSCs promotes DNA demethylation and expression of erythroid genes. Suppressing iron uptake or TET2 expression impairs erythroid genes expression and erythroid differentiation of HSCs; iron supplementation, however, augments these processes. These results establish that the physiological level of iron taken up by HSCs has an instructive role in promoting erythroid-biased differentiation of HSCs.

Keywords

Humans, Spleen, Hematopoietic Stem Cells, Cell Differentiation, Iron, Anemia, Erythroid Cells, DNA-Binding Proteins, Dioxygenases, Haematopoietic stem cells, Stem-cell differentiation, Haematopoietic stem cells

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Associated Data

PMID: 38225226