Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging

Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, such as following infection or inflammation. These challenges impair HSC function, but whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. Unexpectedly, we observed an irreversible depletion of functional HSCs following challenge with inflammation or bacterial infection, with no evidence of any recovery up to 1 year afterward. HSCs from challenged mice demonstrated multiple cellular and molecular features of accelerated aging and developed clinically relevant blood and bone marrow phenotypes not normally observed in aged laboratory mice but commonly seen in elderly humans. In vivo HSC self-renewal divisions were absent or extremely rare during both challenge and recovery periods. The progressive, irreversible attrition of HSC function demonstrates that temporally discrete inflammatory events elicit a cumulative inhibitory effect on HSCs. This work positions early/mid-life inflammation as a mediator of lifelong defects in tissue maintenance and regeneration. [Display omitted] •HSCs fail to recover functional potency after inflammatory/infection challenge•Discrete challenges have a cumulative effect, even if separated by weeks or months•Inflammation in early life accelerates the cellular and molecular aging of HSCs•Mice exposed to inflammation develop features of aged human hematopoiesis Inflammation and infection acutely suppress HSC function. However, the long-term ramifications of such challenges are unclear. This study demonstrates that murine HSCs fail to recover functional potency up to 1 year post-inflammatory/infection challenge, meaning that such events can have accumulative effects over a lifetime; this promotes acquisition of the aged state.