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Aged murine hematopoietic stem cells drive aging-associated immune remodeling

Hanna Leins, Medhanie Mulaw, Karina Eiwen, Vadim Sakk, Ying Liang, Michael Denkinger, Hartmut Geiger and Reinhold Schirmbeck

Key points

  • Phenotypic and functional changes in T- and B-cells of old mice are primarily driven by aging of HSCs.

  • CASIN-treated aged HSCs reconstitute an immune system with a function similar to the one in young animals.

Abstract

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 upon aging are primarily a consequence of changes in the function of HSCs upon 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 re-established an immune system similar to the one 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.

  • Submitted February 1, 2018.
  • Accepted May 30, 2018.