1. An iron rheostat controls hematopoietic stem cell fate.
- Author
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Kao YR, Chen J, Kumari R, Ng A, Zintiridou A, Tatiparthy M, Ma Y, Aivalioti MM, Moulik D, Sundaravel S, Sun D, Reisz JA, Grimm J, Martinez-Lopez N, Stransky S, Sidoli S, Steidl U, Singh R, D'Alessandro A, and Will B
- Subjects
- Hematopoietic Stem Cells metabolism, Multipotent Stem Cells metabolism, Gene Expression Regulation, Cell Differentiation, Hematopoiesis genetics, Iron metabolism
- 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., Competing Interests: Declaration of interests B.W. and U.S. have received funds for research projects and for serving on the advisory board of Novartis Pharmaceuticals., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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