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

Ruzhica Bogeska, Ana Matea Mikecin, Paul Kaschutnig, Malak Fawaz, Marleen Büchler-Schäff, Duy Le, Miguel Ganuza, Angelika Vollmer, Stella V. Paffenholz, Noboru Asada, Esther Rodriguez-Correa, Felix Frauhammer, Florian Buettner, Melanie Ball, Julia Knoch, Sina Stäble, Dagmar Walter, Amelie Petri, Martha J. Carreño-Gonzalez, Vinona WagnerBenedikt Brors, Simon Haas, Daniel B. Lipka, Marieke A.G. Essers, Vivienn Weru, Tim Holland-Letz, Jan Philipp Mallm, Karsten Rippe, Stephan Krämer, Matthias Schlesner, Shannon McKinney Freeman, Maria Carolina Florian, Katherine Y. King, Paul S. Frenette, Michael A. Rieger, Michael D. Milsom

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1273-1284.e8
JournalCell stem cell
Volume29
Issue number8
DOIs
Publication statusPublished - Aug 4 2022
Externally publishedYes

Keywords

  • accelerated aging
  • aging
  • clonal hematopoiesis
  • hematopoietic stem cells
  • HSCs
  • inflammaging
  • inflammation
  • self-renewal
  • stem cell exhaustion
  • stress hematopoiesis

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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