Abstract
Inflammation activates many blood cell types, driving aging and malignancy. Yet, hematopoietic stem cells (HSCs) survive a lifetime of infection to sustain life-long blood production. To understand HSC adaptation to inflammation, we developed xenograft inflammation-recovery models and performed single cell multiomics on isolated human HSC. Two transcriptionally and epigenetically distinct HSC subsets expressing canonical HSC programs were identified. Only one showed sustained transcriptional and epigenetic changes after recovery from inflammatory treatments. This HSC inflammatory memory (HSC-iM) program is enriched in memory T cells and HSCs from recovered COVID-19 patients. Importantly, HSC-iM accumulates with age and with clonal hematopoiesis. Overall, heritable molecular alterations in a subset of human HSCs, an adaptation to long-term inflammatory stress, may predispose to heightened age-related risk of blood cancer and infection.
One-Sentence Summary Inflammation across a lifetime rewires human HSCs to produce a distinct HSC subset with both beneficial and deleterious fitness consequences.
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.
Footnotes
↵‡ Co-senior authors
Updated main text and main figures; Updated author list; Supplemental methods and figures now included.