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

作者：Ruzhica Bogeska, A. Mikecin, P. Kaschutnig, Malak Fawaz, Marleen Büchler-Schäff, D. Le, Miguel Ganuza, A. Vollmer, Stella V. Paffenholz, N. Asada, E. Rodríguez-Correa, F. Frauhammer, F. Buettner, M. Ball, J. Knoch, Sina Stäble, D. Walter, Amelie Petri, Martha J. Carreño-Gonzalez, Vinona Wagner, B. Brors, S. Haas, D. Lipka, M. Essers, V. Weru, T. Holland-Letz, Jan-Philipp Mallm, K. Rippe, Stephan M. Krämer, M. Schlesner, Shannon L McKinney Freeman, M. Florian, K. King, P. Frenette, M. Rieger, M. Milsom · 发表于：Cell Stem Cell · 年份：2022 · DOI：10.1016/j.stem.2022.06.012 · 被引用次数：246 · 研究领域：Medicine

Summary: 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 one year afterwards. 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.