美国哈佛大学Vijay G. Sankaran研究小组揭示人类造血干细胞对铁死亡的脆弱性。2023年2月16日出版的《细胞》杂志发表了这项成果。

受组蛋白去泛素酶MYSM1缺失引起的骨髓衰竭疾病的启发，并以选择性不利的造血干细胞为特征，研究人员人员展示了造血干细胞（HSC）中蛋白质合成减少如何导致铁死亡增加。尽管蛋白质合成速率没有改变，但阻止铁死亡可以完全挽救HSC的维持。重要的是，这种铁死亡的选择性脆弱性不仅是MYSM1缺陷中HSC损失的基础，而且是人类HSC更广泛责任的特征。通过MYSM1过表达增加蛋白质合成速率，使HSC对铁死亡不那么敏感，这更广泛地说明了生理适应导致体细胞干细胞群体中出现的选择性脆弱性。

据了解，HSC具有许多独特的生理适应，能够终身维持血细胞生产，包括高度调控的蛋白质合成速率。然而，这种适应所产生的确切脆弱性还没有完全被描述出来。

附：英文原文

Title: Human hematopoietic stem cell vulnerability to ferroptosis

Author: Jiawei Zhao, Yuemeng Jia, Dilnar Mahmut, Amy A. Deik, Sarah Jeanfavre, Clary B. Clish, Vijay G. Sankaran

Issue&Volume: 2023/02/16

Abstract: Hematopoietic stem cells (HSCs) have a number of unique physiologic adaptations that enable lifelong maintenance of blood cell production, including a highly regulated rate of protein synthesis. Yet, the precise vulnerabilities that arise from such adaptations have not been fully characterized. Here, inspired by a bone marrow failure disorder due to the loss of the histone deubiquitinase MYSM1, characterized by selectively disadvantaged HSCs, we show how reduced protein synthesis in HSCs results in increased ferroptosis. HSC maintenance can be fully rescued by blocking ferroptosis, despite no alteration in protein synthesis rates. Importantly, this selective vulnerability to ferroptosis not only underlies HSC loss in MYSM1 deficiency but also characterizes a broader liability of human HSCs. Increasing protein synthesis rates via MYSM1 overexpression makes HSCs less susceptible to ferroptosis, more broadly illustrating the selective vulnerabilities that arise in somatic stem cell populations as a result of physiologic adaptations.

DOI: 10.1016/j.cell.2023.01.020

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00050-8