Abstract
Mechanisms governing the maintenance of blood-producing hematopoietic stem and multipotent progenitor cells (HSPCs) are incompletely understood, particularly those regulating fate, ensuring long-term maintenance, and preventing aging-associated stem cell dysfunction. We uncovered a role for transitory free cytoplasmic iron as a rheostat for adult stem cell fate control. We found that HSPCs harbor comparatively small amounts of free iron and show the activation of a conserved molecular response to limited iron—particularly during mitosis. To study the functional and molecular consequences of iron restriction, we developed models allowing for transient iron bioavailability limitation and combined single-molecule RNA quantification, metabolomics, and single-cell transcriptomic analyses with functional studies. Our data reveal that the activation of the limited iron response triggers coordinated metabolic and epigenetic events, establishing stemness-conferring gene regulation. Notably, we find that aging-associated cytoplasmic iron loading reversibly attenuates iron-dependent cell fate control, explicating intervention strategies for dysfunctional aged stem cells.
Original language | English (US) |
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Pages (from-to) | 378-397.e12 |
Journal | Cell Stem Cell |
Volume | 31 |
Issue number | 3 |
DOIs | |
State | Published - Mar 7 2024 |
Keywords
- Tip60/KAT5
- aging
- gene regulation
- hematopoiesis
- iron
- metabolism
- stem cells
ASJC Scopus subject areas
- Molecular Medicine
- Genetics
- Cell Biology