Human haematopoietic stem cells remember inflammatory stress
- Andy G. X. Zeng
- Murtaza S. Nagree
- Niels Asger Jakobsen
- Sayyam Shah
- Angelica Varesi
- Jasmine Ryu Won Kang
- Alex Murison
- Jin-Gyu Cheong
- Sven Turkalj
- Xuan Zhang
- Felix A. Radtke
- Tsega-Ab Abera
- Isabel N. X. Lim
- Liqing Jin
- Joana Araújo
- Alicia G. Aguilar-Navarro
- Darrien Parris
- Jessica McLeod
- Hyerin Kim
- Ho Seok Lee
- Lin Zhang
- Mason Boulanger
- Elyssa Bader
- Elias Gbeha
- Christopher N. Parkhurst
- Elvin Wagenblast
- Eugenia Flores-Figueroa
- Bo Wang
- Gregory W. Schwartz
- Leonard D. Shultz
- Anna S. Nam
- H. Leighton Grimes
- Steven Z. Josefowicz
- Philip Awadalla
- Paresh Vyas
- John E. Dick
- Stephanie Z. Xie
2026-05-27
Inflammation activates blood cells, contributing to ageing and malignancy 1–3 . Haematopoietic stem cells (HSCs) survive a lifetime of infection to sustain life-long haematopoiesis 1–9 , but how human HSCs respond and adapt to inflammatory stress is largely unknown. Here, to empirically understand this adaptation, we developed xenograft inflammation–recovery models and performed single-cell multiomics on xenografted human HSCs. Two transcriptionally and epigenetically distinct HSC subsets were identified with one, termed HSC inflammatory memory (HSC-iM), retaining a molecular memory of previous inflammatory treatments. The HSC-iM subset exhibited quiescence and restrained haematopoietic output. Molecularly, the HSC-iM program was enriched in HSCs from adult and paediatric samples across conditions ranging from COVID-19 recovery, sickle cell disease, ageing and clonal haematopoiesis, establishing both the validity of our xenograft models and the physiological relevance of HSC-iM. Clonal haematopoiesis mutations in HSC-iM attenuated the effects of inflammatory stress by promoting HSC activation and differentiation. Moreover, transmission of the pro-inflammatory HSC-iM transcriptional program to differentiated immune progeny was demonstrated in xenograft and physiological settings. Finally, HSC-iM program enrichment in circulating blood cells was associated with a heightened risk score for all-cause mortality in population cohort analyses, underscoring the clinical relevance of this newly identified HSC subset in characterizing heterogeneous health outcomes across a lifetime.