Author:
Zeng Andy G.X.,Nagree Murtaza S.,Jakobsen Niels Asger,Shah Sayyam,Murison Alex,Cheong Jin-Gyu,Turkalj Sven,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,Wagenblast Elvin,Flores-Figueroa Eugenia,Wang Bo,Schwartz Gregory W.,Shultz Leonard D.,Josefowicz Steven Z.,Vyas Paresh,Dick John E.,Xie Stephanie Z.
Abstract
AbstractInflammation 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 SummaryInflammation across a lifetime rewires human HSCs to produce a distinct HSC subset with both beneficial and deleterious fitness consequences.
Publisher
Cold Spring Harbor Laboratory