biostudies-literatureKao YRNIA NIH HHSNIDDK NIH HHSNHLBI NIH HHSNCI NIH HHSNational Institutes of Health378-397.e12https://www.ebi.ac.uk/biostudies/studies/S-EPMC10939794biostudies-literatureUnknown31(3)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.Cell stem cellAn iron rheostat controls hematopoietic stem cell fate.PMC10939794R35 CA253127P30 CA013330T32 AG023475R01 DK123327R01 CA230756RF1 AG043517R01 HL146442K00 CA223044R01 HL148151R01 HL157948D'Alessandro AMartinez-Lopez NKao YRChen JStransky SSteidl UMoulik DMa YSundaravel SSidoli STatiparthy MReisz JAGrimm JZintiridou AAivalioti MMSun DKumari RSingh RWill BNg AfalseAn iron rheostat controls hematopoietic stem cell fate.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.2024-01-01T00:00:00Z2024 Mar2026-06-01T22:06:41.476Z2025-04-04T02:12:24.222ZS-EPMC109397943840261710.1016/j.stem.2024.01.011