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.

中文翻译：

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铁变阻器控制造血干细胞的命运


控制造血干细胞和多能祖细胞（HSPC）维持的机制尚不完全清楚，特别是那些调节命运、确保长期维持和预防与衰老相关的干细胞功能障碍的机制。我们发现了短暂游离细胞质铁作为成体干细胞命运控制变阻器的作用。我们发现 HSPC 含有相对少量的游离铁，并表现出对有限铁的保守分子反应的激活——尤其是在有丝分裂期间。为了研究铁限制的功能和分子后果，我们开发了允许短暂铁生物利用度限制的模型，并将单分子 RNA 定量、代谢组学和单细胞转录组分析与功能研究相结合。我们的数据表明，有限铁反应的激活会触发协调的代谢和表观遗传事件，从而建立赋予干性的基因调控。值得注意的是，我们发现与衰老相关的细胞质铁负荷可逆地减弱铁依赖性细胞命运控制，阐明了功能失调的衰老干细胞的干预策略。