Increased iron uptake by splenic hematopoietic stem cells promotes TET2-dependent erythroid regeneration

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 and Daisuke Nakada ()
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Yu-Jung Tseng: Baylor College of Medicine
Yuki Kageyama: Baylor College of Medicine
Rebecca L. Murdaugh: Baylor College of Medicine
Ayumi Kitano: Baylor College of Medicine
Jong Hwan Kim: Baylor College of Medicine
Kevin A. Hoegenauer: Baylor College of Medicine
Jonathan Tiessen: Baylor College of Medicine
Mackenzie H. Smith: Baylor College of Medicine
Hidetaka Uryu: The University of Texas MD Anderson Cancer Center
Koichi Takahashi: The University of Texas MD Anderson Cancer Center
James F. Martin: Baylor College of Medicine
Md Abul Hassan Samee: Baylor College of Medicine
Daisuke Nakada: Baylor College of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-44718-0

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