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<p>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.</p>

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Inhibiting ferroptosis enhances ex vivo expansion of human haematopoietic stem cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月18日

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

摘要

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.