近日，美国爱因斯坦医学院Britta Will等研究人员合作发现，一个铁离子变阻器控制造血干细胞的命运。2024年2月22日，国际知名学术期刊《细胞—干细胞》在线发表了这一成果。

研究人员发现了过渡性游离细胞质铁在成体干细胞命运控制中的作用。研究人员发现，造血干细胞和多潜能祖细胞（HSPC）蕴藏着相对少量的游离铁，并对有限的铁（特别是在有丝分裂期间）显示出保守的分子反应激活。为了研究铁限制的功能和分子后果，研究人员开发了允许瞬时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。

数据显示，铁限制反应的激活引发了协调的代谢和表观遗传事件，建立了干性强化基因调控。值得注意的是，研究人员发现衰老相关的细胞质铁负荷会可逆地削弱铁依赖的细胞命运控制，从而解释了针对功能失调的衰老干细胞的干预策略。

研究人员表示，人们对HSPC的维持机制尚不完全了解，特别是那些调节命运、确保长期维持和防止衰老相关干细胞功能障碍的机制。

附：英文原文

Title: An iron rheostat controls hematopoietic stem cell fate

Author: Yun-Ruei Kao, Jiahao Chen, Rajni Kumari, Anita Ng, Aliona Zintiridou, Madhuri Tatiparthy, Yuhong Ma, Maria M. Aivalioti, Deeposree Moulik, Sriram Sundaravel, Daqian Sun, Julie A. Reisz, Juliane Grimm, Nuria Martinez-Lopez, Stephanie Stransky, Simone Sidoli, Ulrich Steidl, Rajat Singh, Angelo D’Alessandro, Britta Will

Issue&Volume: 2024-02-22

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.

DOI: 10.1016/j.stem.2024.01.011

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(24)00041-9