Human haematopoietic stem cells remember inflammatory stress

, 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.

Authors

Institutions

Publication Details

Journal
Nature
Published
2026-05-27
DOI
https://doi.org/10.1038/s41586-026-10522-7
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Human haematopoietic stem cells remember inflammatory stress

Philip Awadalla, Sven Turkalj, Ho Seok Lee, Isabel N.X. Lim et al.
Nature
Single-cell and spatial transcriptomics
article

Human haematopoietic stem cells remember inflammatory stress

Philip Awadalla, Sven Turkalj, Ho Seok Lee, Isabel N.X. Lim, Angelica Varesi, Christopher N. Parkhurst, Sayyam Shah, Darrien Parris, Elvin Wagenblast, Niels Asger Jakobsen, Liqing Jin, Alicia G. Aguilar-Navarro, Andy G.X. Zeng, Felix A. Radtke, Bo Wang, Elias Gbeha, Murtaza S. Nagree, John E. Dick, Gregory W. Schwartz, Joana Araújo, J. KANG, Anna S. Nam, Steven Z. Josefowicz, Elyssa Bader, Mason Boulanger, Eugenia Flores-Figueroa, Stephanie Z. Xie, Jessica McLeod, Xuan Zhang, H. Leighton Grimes, Paresh Vyas, Lin Zhang, Jin-Gyu Cheong, Leonard D. Shultz, Alex Murison, Tsega-Ab Abera, Hyerin Kim
article en

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.

Nature
Ontario Institute for Cancer Research (CA), Cincinnati Children's Hospital Medical Center (US), Boston Children's Hospital (US), University Health Network (CA), Simon Fraser University (CA), Universidade do Porto (PT), University of Toronto (CA), Cornell University (US), Princess Margaret Cancer Centre (CA), Hospital de São João (PT), University of Oxford (GB), MRC Weatherall Institute of Molecular Medicine (GB), Jackson Laboratory (US), Dana-Farber Cancer Institute (US), Vector Institute (CA), Oxford BioMedica (United Kingdom) (GB), Oxford University Hospitals NHS Trust (GB), i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto (PT), Weill Cornell Medicine (US), Icahn School of Medicine at Mount Sinai (US)
Responsible consumption and production
Openalex Percentile: Top 10%
Single-cell and spatial transcriptomics
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.