麻省理工学院和哈佛大学的布罗德研究所Vijay G. Sankaran课题组的一项最新研究揭示了抑制铁死亡可增强人造血干细胞的体外扩增。这一研究成果于2025年11月18日发表在国际顶尖学术期刊《自然—细胞生物学》上。

在这里，该研究团队表明这种磨损主要是由铁死亡驱动的，铁死亡是一种代谢调节的、铁依赖性的细胞死亡途径，它可以被阻断以增加HSC的扩增。在广泛主题的无血清培养和最近报道的化学定义条件下，用利普司他汀-1或他汀-1抑制铁死亡显著增加脐带血和成人造血干细胞在供体中的扩张。扩增后的细胞保留了表型和分子干细胞的特性，并介导了在异种移植小鼠中持久的多系植入，而没有遗传毒性或异常造血。

在机制上，铁死亡阻断伴随着核糖体生物发生和胆固醇合成的上调，7-脱氢胆固醇水平的增加，7-脱氢胆固醇是一种有效的内源性铁死亡抑制剂，它本身促进HSC扩张。至关重要的是，这种方法提高了治疗性基因组修饰造血干细胞的产量，为临床应用铺平了道路。

据介绍，人类造血干细胞（HSC）体外扩增的改进将大大推进移植和基因组工程治疗，然而现有的培养方法仍然允许大量HSC丢失。

附：英文原文

Title: Inhibiting ferroptosis enhances ex vivo expansion of human haematopoietic stem cells

Author: della Volpe, Lucrezia, Lee, Andrew J., Antoszewski, Mateusz, Deik, Amy A., Safina, Ksenia R., Gao, Teng, Guo, Chun-Jie, Ye, Tianyi, Lyu, Peng, Martin-Rufino, Jorge D., Castano, Nicole, Good, Jonathan, Molina-Aponte, Yaniris, Zhao, Jiawei, Clish, Clary B., van Galen, Peter, Sankaran, Vijay G.

Issue&Volume: 2025-11-18

Abstract: Improved ex vivo expansion of human haematopoietic stem cells (HSCs) would considerably advance transplantation and genome-engineered therapies, yet existing culture methods still allow substantial HSC loss. Here we show that this attrition is driven largely by ferroptosis, a metabolically regulated, iron-dependent cell-death pathway, and that it can be blocked to augment HSC expansion. Inhibiting ferroptosis with liproxstatin-1 or ferrostatin-1 markedly increases the expansion of cord blood and adult HSCs consistently across donors in both widely used serum-free cultures and recently reported chemically defined conditions. The expanded cells retain phenotypic and molecular stem cell identity and mediate improved durable, multilineage engraftment in xenotransplanted mice without genotoxicity or aberrant haematopoiesis. Mechanistically, ferroptosis blockade is accompanied by upregulated ribosome biogenesis and cholesterol synthesis, increasing levels of 7-dehydrocholesterol—a potent endogenous ferroptosis inhibitor that itself promotes HSC expansion. Crucially, this approach enhances yields of therapeutically genome-modified HSCs, paving a path for clinical applications.

DOI: 10.1038/s41556-025-01814-7

Source: https://www.nature.com/articles/s41556-025-01814-7