Aging-associated remodeling of the immune system impairs its functional integrity and contributes to increased morbidity and mortality in the elderly. Aging of hematopoietic stem cells (HSCs), from which all cells of the adaptive immune system ultimately originate, might play a crucial role in the remodeling of the aged immune system. We recently reported that aging of HSCs is, in part, driven by elevated activity of the small RhoGTPase Cdc42 and that aged HSCs can be rejuvenated in vitro by inhibition of the elevated Cdc42 activity in aged HSCs with the pharmacological compound CASIN. To study the quality of immune systems stemming selectively from young or aged HSCs, we established a HSC transplantation model in T- and B-cell-deficient young RAG1−/− hosts. We report that both phenotypic and functional changes in the immune system on aging are primarily a consequence of changes in the function of HSCs on aging and, to a large extent, independent of the thymus, as young and aged HSCs reconstituted distinct T- and B-cell subsets in RAG1−/− hosts that mirrored young and aged immune systems. Importantly, aged HSCs treated with CASIN reestablished an immune system similar to that of young animals, and thus capable of mounting a strong immune response to vaccination. Our studies further imply that epigenetic signatures already imprinted in aged HSCs determine the transcriptional profile and function of HSC-derived T and B cells.
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This work was supported by grants from the Bundesministerium für Bildung und Forschung (systems biology analysis of impaired stem cell function and regeneration during aging [SyStaR]) (H.G. and M.D.) and from the Deutsche Forschungsgemeinschaft Graduiertenkolleg (GRK) 1789 Cellular and Molecular Mechanisms in Aging (H.G. and R.S.). The laboratory of H.G. was further supported by National Institutes of Health grants HL076604, DK077762, AG040118, and DK104814; the Deutsche Forschungsgemeinschaft (GRK 2254 HEIST and SFBs 1074, 1149, and 1275); and the Excellence-Initiative of the Baden-Württemberg Foundation. The laboratory of R.S. was further supported by grants from the Deutsche Forschungsgemeinschaft (GRK 2254 HEIST; SCHI505/6-1) and the Böhringer Ingelheim Ulm University Bio Center.
The online version of this article contains a data supplement.
Leins, Hanna; Mulaw, Medhanie; Eiwen, Karina; Sakk, Vadim; Liang, Ying; Denkinger, Michael; Geiger, Hartmut; and Schirmbeck, Reinhold, "Aged Murine Hematopoietic Stem Cells Drive Aging-Associate Immune Remodeling" (2018). Toxicology and Cancer Biology Faculty Publications. 77.