人造血干细胞对铁死亡的易感性。
Human hematopoietic stem cell vulnerability to ferroptosis.
机构信息
Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
出版信息
Cell. 2023 Feb 16;186(4):732-747.e16. doi: 10.1016/j.cell.2023.01.020.
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.
造血干细胞（HSCs）具有许多独特的生理适应性，使其能够终生维持血细胞的产生，包括高度调节的蛋白质合成率。然而，这些适应性所带来的确切脆弱性尚未得到充分描述。在这里，受由于组蛋白去泛素酶 MYSM1 缺失导致的骨髓衰竭障碍的启发，该障碍的特征是 HSCs 选择性处于不利地位，我们展示了 HSCs 中蛋白质合成减少如何导致铁死亡增加。尽管蛋白质合成率没有改变，但阻断铁死亡可以完全挽救 HSC 的维持。重要的是，这种对铁死亡的选择性脆弱性不仅是 MYSM1 缺陷导致 HSC 丢失的基础，而且还表征了人类 HSCs 的更广泛的易损性。通过过表达 MYSM1 增加蛋白质合成率，使 HSCs 对铁死亡的敏感性降低，更广泛地说明了生理适应性导致体细胞干细胞群体中出现的选择性脆弱性。
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