A hematopoietic stem cell subset that retains memory of prior inflammatory stress accumulates in aging and clonal hematopoiesis

Hematopoietic stem cells (HSC) must persist through a lifetime of infections to ensure life-long blood production, but whether molecular adaptations following inflammatory stress recovery in HSC are linked to aging and clonal hematopoiesis (CH) are unclear. Here, we performed single cell (sc) Multiomics on human HSC isolated from a xenograft inflammation-recovery model. Two transcriptionally and epigenetically distinct HSC subsets expressing canonical HSC programs were identified. Only one showed scATACseq and scRNAseq changes after recovery from TNFα or lipopolysaccharide treatment. This inflammatory memory HSC (HSC-iM) program is enriched in memory T cells and HSC from recovered COVID-19 patients. Importantly, HSC-iM accumulates with age and with CH. Overall, a human HSC subset that retains memory of prior inflammatory stress has implications towards HSC fitness and leukemia transformation. ### Competing Interest Statement J.E.D. serves on the SAB for Graphite Bio, receives royalties from Trillium Therapeutics Inc/Pfizer and receives a commercial research grant from Celgene/BMS. The remaining authors declare no competing interests.