Hematopoietic stem cells activate a latent differentiation pathway to facilitate recovery after 5-fluorouracil-induced myeloablation.

IF 9.2 1区生物学 Q1 CELL BIOLOGY

Developmental cell Pub Date : 2026-05-13 Epub Date: 2026-03-02 DOI:10.1016/j.devcel.2026.02.003

Zhen Zhang, Ben Jin, Chenyu You, Ya Li, Li Lin, Jianlong Sun

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Abstract

Myeloablative chemotherapy induces hematopoietic regeneration, a process orchestrated by hematopoietic stem cells (HSCs). Although prior studies have documented enhanced HSC differentiation during this process, the temporal changes in HSC fate in response to such stress remain unclear. Here, we employed lineage tracing and mathematical modeling to investigate the cell-fate dynamics of Endothelial Protein C Receptor (EPCR)-high HSCs following 5-fluorouracil (5-FU)-induced myeloablation. Our analysis revealed a transient surge in HSC differentiation immediately after 5-FU treatment, generating primarily myeloid-biased multipotent progenitors (MPPs)-subsets that typically receive limited HSC input under steady-state conditions. Following this initial cell-fate switch, elevated HSC differentiation persisted but rapidly reverted to the homeostatic differentiation pattern observed in unperturbed hematopoiesis. Additionally, our data highlight a substantial contribution of MPPs to myeloid and lymphoid lineage regeneration following 5-FU challenge. Together, these findings delineate the sequential fate transitions adopted by HSCs during severe myeloablation and identify stage-specific differentiation patterns of HSCs in stress hematopoiesis.

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造血干细胞激活潜在分化途径，促进5-氟尿嘧啶诱导骨髓消融后的恢复。

骨髓清除化疗诱导造血再生，这是一个由造血干细胞（hsc）协调的过程。尽管先前的研究已经证实在这一过程中增强了HSC分化，但HSC命运在这种应激反应中的时间变化尚不清楚。在这里，我们采用谱系追踪和数学模型来研究内皮蛋白C受体（EPCR）高造血干细胞在5-氟尿嘧啶（5-FU）诱导骨髓消融后的细胞命运动态。我们的分析显示，在5-FU治疗后，HSC分化立即出现短暂的激增，主要产生骨髓偏向性多能祖细胞（mpp），这些亚群通常在稳态条件下接受有限的HSC输入。在这种初始的细胞命运转换之后，升高的HSC分化持续存在，但迅速恢复到在未受干扰的造血中观察到的稳态分化模式。此外，我们的数据强调了mpp对5-FU挑战后髓系和淋巴系再生的重大贡献。总之，这些发现描述了造血干细胞在严重骨髓消融过程中所采用的顺序命运转变，并确定了应激造血中造血干细胞的阶段特异性分化模式。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Developmental cell 生物-发育生物学

CiteScore

18.90

自引率

1.70%

发文量

203

审稿时长

3-6 weeks

期刊介绍： Developmental Cell, established in 2001, is a comprehensive journal that explores a wide range of topics in cell and developmental biology. Our publication encompasses work across various disciplines within biology, with a particular emphasis on investigating the intersections between cell biology, developmental biology, and other related fields. Our primary objective is to present research conducted through a cell biological perspective, addressing the essential mechanisms governing cell function, cellular interactions, and responses to the environment. Moreover, we focus on understanding the collective behavior of cells, culminating in the formation of tissues, organs, and whole organisms, while also investigating the consequences of any malfunctions in these intricate processes.