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