Human haematopoietic stem cells remember inflammatory stress
Inflammation activates blood cells, contributing to ageing and malignancy1,2,3. Haematopoietic stem cells (HSCs) survive a lifetime of infection to sustain life-long haematopoiesis1,2,3,4,5,6,7,8,9, 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.
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Zeng, Andy G X; Nagree, Murtaza S; Jakobsen, Niels Asger; Shah, Sayyam; Varesi, Angelica; Kang, Jasmine Ryu Won; Murison, Alex; Cheong, Jin-Gyu; Turkalj, Sven; Zhang, Xuan; Radtke, Felix A; Abera, Tsega-Ab; Lim, Isabel N X; Jin, Liqing; Araújo, Joana; Aguilar-Navarro, Alicia G; Parris, Darrien; McLeod, Jessica; Kim, Hyerin; Lee, Ho Seok; Zhang, Lin; Boulanger, Mason; Bader, Elyssa; Gbeha, Elias; Parkhurst, Christopher N; Wagenblast, Elvin; Flores-Figueroa, Eugenia; Wang, Bo; Schwartz, Gregory W; Shultz, Leonard D; Nam, Anna S; Grimes, H Leighton; Josefowicz, Steven Z; Awadalla, Philip; Vyas, Paresh; Dick, John E; Xie, Stephanie Z
Inflammation activates blood cells, contributing to ageing and malignancy1,2,3. Haematopoietic stem cells (HSCs) survive a lifetime of infection to sustain life-long haematopoiesis1,2,3,4,5,6,7,8,9, 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.
Web | DOI | PDF | Nature | Open Access