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Peer-reviewedCC BYNature

Human haematopoietic stem cells remember inflammatory stress

  • Andy G.X. Zeng1,2
  • Murtaza S. Nagree2
  • Niels Asger Jakobsen3,4
  • Sayyam Shah2,5
  • Angelica Varesi1,2
  • Jasmine Ryu Won Kang1,6,2
  • Alex Murison2
  • Jin‐Gyu Cheong7,8
  • Sven Turkalj9,3,4
  • Xuan Zhang10
  • Felix A. Radtke3,4
  • Tsega‐Ab Abera7
25 more authors
  • Isabel N.X. Lim2
  • Liqing Jin2
  • Joana Araújo11,12,13,14
  • Alicia G. Aguilar-Navarro2
  • Darrien Parris2
  • Jessica McLeod2
  • Hyerin Kim2
  • Ho Seok Lee2
  • Lin Zhang15,16
  • Mason Boulanger2
  • Elyssa Bader1,6
  • Elias Gbeha6
  • Christopher N. Parkhurst17
  • Elvin Wagenblast18,2
  • Eugenia Flores Figueroa2
  • Bo Wang19,20,16,21
  • Gregory W. Schwartz22,2
  • Leonard D. Shultz23
  • Anna S. Nam7
  • H. Leighton Grimes24
  • Steven Zvi Josefowicz7,8
  • Philip Awadalla25
  • Paresh Vyas26,3,4
  • John Edgar Dick1,2
  • Stephanie Zhi-Juan Xie27,28
28 affiliations
  1. 1Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  2. 2Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
  3. 3MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
  4. 4NIHR Oxford Biomedical Research Centre, Oxford, UK
  5. 5Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  6. 6Ontario Institute for Cancer Research, Toronto, Ontario, Canada
  7. 7Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
  8. 8Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School, NewYork, NY, USA
  9. 9Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, USA
  10. 10Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
  11. 11Department of Hematology, Centro Hospitalar Universitário de São João, Porto, Portugal
  12. 12Faculty of Medicine, University of Porto, Porto, Portugal
  13. 13Instituto Nacional de Investigação Biomédica, University of Porto, Porto, Portugal
  14. 14Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
  15. 15Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, British Columbia, Canada
  16. 16Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
  17. 17Division of Pulmonary and Critical Care Medicine, Weill Cornell Graduate School, NewYork, NY, USA
  18. 18Icahn School of Medicine at Mount Sinai, New York, NY, USA
  19. 19Department of Computer Science, University of Toronto, Toronto, Ontario, Canada
  20. 20Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  21. 21Vector Institute, Toronto, Ontario, Canada
  22. 22Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
  23. 23The Jackson Laboratory, Bar Harbor, ME, USA
  24. 24Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA
  25. 25Nuffield Department of Population Health, Big Data Institute, University of Oxford, Oxford, UK
  26. 26Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  27. 27Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [email protected]
  28. 28Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [email protected]
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Abstract

, 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.

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Cite

BibTeXRIS
BibTeX
@article{zeng2026human,
  title = {{Human haematopoietic stem cells remember inflammatory stress}},
  author = {Andy G.X. Zeng and Murtaza S. Nagree and Niels Asger Jakobsen and Sayyam Shah and Angelica Varesi and Jasmine Ryu Won Kang and Alex Murison and Jin‐Gyu Cheong and Sven Turkalj and Xuan Zhang and Felix A. Radtke and Tsega‐Ab Abera and Isabel N.X. Lim and Liqing Jin and Joana Araújo and Alicia G. Aguilar-Navarro and Darrien Parris and Jessica McLeod and Hyerin Kim and Ho Seok Lee and Lin Zhang and Mason Boulanger and Elyssa Bader and Elias Gbeha and Christopher N. Parkhurst and Elvin Wagenblast and Eugenia Flores Figueroa and Bo Wang and Gregory W. Schwartz and Leonard D. Shultz and Anna S. Nam and H. Leighton Grimes and Steven Zvi Josefowicz and Philip Awadalla and Paresh Vyas and John Edgar Dick and Stephanie Zhi-Juan Xie},
  journal = {Nature},
  year = {2026},
  month = may,
  doi = {10.1038/s41586-026-10522-7},
  url = {https://doi.org/10.1038/s41586-026-10522-7},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Human haematopoietic stem cells remember inflammatory stress
AU  - Andy G.X. Zeng
AU  - Murtaza S. Nagree
AU  - Niels Asger Jakobsen
AU  - Sayyam Shah
AU  - Angelica Varesi
AU  - Jasmine Ryu Won Kang
AU  - Alex Murison
AU  - Jin‐Gyu Cheong
AU  - Sven Turkalj
AU  - Xuan Zhang
AU  - Felix A. Radtke
AU  - Tsega‐Ab Abera
AU  - Isabel N.X. Lim
AU  - Liqing Jin
AU  - Joana Araújo
AU  - Alicia G. Aguilar-Navarro
AU  - Darrien Parris
AU  - Jessica McLeod
AU  - Hyerin Kim
AU  - Ho Seok Lee
AU  - Lin Zhang
AU  - Mason Boulanger
AU  - Elyssa Bader
AU  - Elias Gbeha
AU  - Christopher N. Parkhurst
AU  - Elvin Wagenblast
AU  - Eugenia Flores Figueroa
AU  - Bo Wang
AU  - Gregory W. Schwartz
AU  - Leonard D. Shultz
AU  - Anna S. Nam
AU  - H. Leighton Grimes
AU  - Steven Zvi Josefowicz
AU  - Philip Awadalla
AU  - Paresh Vyas
AU  - John Edgar Dick
AU  - Stephanie Zhi-Juan Xie
PY  - 2026
DA  - 2026/05/27
JO  - Nature
DO  - 10.1038/s41586-026-10522-7
UR  - https://doi.org/10.1038/s41586-026-10522-7
AB  - , 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.
SN  - 0028-0836
SN  - 1476-4687
ER  -