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

  • Dev Cell. 2026 May 13;61(5):1044-1060.e7. doi: 10.1016/j.devcel.2026.02.003.
Zhen Zhang  1 ,  Ben Jin  1 ,  Chenyu You  1 ,  Ya Li  1 ,  Li Lin  2 ,  Jianlong Sun  3
Affiliations
  • 1. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 2. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: [email protected].
  • 3. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China. Electronic address: [email protected].
PMID: 41775265 DOI: 10.1016/j.devcel.2026.02.003
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.

Keywords
5-fluorouracil; hematopoietic stem cell; lineage tracing; stress hematopoiesis.
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