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

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.