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Identification of a human hematopoietic stem cell subset that retains memory of inflammatory stress [TARGET-seq}

ABSTRACT: Inflammation activates blood cells, driving aging and malignancy. Hematopoietic stem cells (HSCs) survive a lifetime of infection, sustaining life-long hematopoiesis. Yet, how human HSCs respond and adapt to inflammatory stress is largely unknown. We developed xenograft inflammation-recovery models and performed single-cell multiomics on human HSCs to empirically understand HSC adaptation to inflammatory stress. Two transcriptionally and epigenetically distinct HSC subsets were identified with one, termed HSC inflammatory memory (HSC-iM), retaining molecular memory of prior inflammatory treatments. The HSC-iM molecular program was enriched in HSC from adult and pediatric samples across conditions ranging from COVID-19 recovery, aging, sickle cell disease, and clonal hematopoiesis (CH), establishing both the validity of our xenograft models and the physiological relevance of HSC-iM. The HSC-iM subset exhibited quiescence, hallmark inflammatory signatures, restrained hematopoietic output, and the transmission of the pro-inflammatory HSC-iM transcriptional program to downstream myelo-lymphoid progeny. These heritable molecular alterations represent an adaptation to inflammatory stress and some were found to be relieved by CH mutation acquisition. Finally, HSC-iM programs in circulating blood cells were associated with a risk score for all-cause mortality in population cohort analyses, underscoring the importance of this newly identified HSC subset in characterizing heterogeneous health outcomes across a lifetime.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317773 | GEO | 2026/03/09

REPOSITORIES: GEO

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