Hematopoietic stem cells in the bone marrow generate red blood cells and immune cells. Immune cells can be roughly divided into myeloid lineages of the innate immune system and lymphoid lineages of the adaptive immune system. With advancing age, the generation of myeloid cells becomes favored over lymphoid cells, and this is one source of dysfunction in the aged immune system. Here, researchers find a signature of age-related dysfunction in hematopoietic cells that favor myeloid cell production. This could be a first step towards targeting these malfunctioning hematopoietic cells in order to restore a more balanced generation of immune cells and thus improve immune function in older individuals.
Hematopoietic stem cells (HSCs) exhibit significant age-related phenotypic and functional alterations. Although single-cell technologies have elucidated age-related compositional changes, prospective identification of aging-associated HSC subsets has remained challenging. In this study, utilizing Clusterin (Clu)-GFP reporter mice, we demonstrated that Clu expression faithfully marks age-associated myeloid/platelet-biased HSCs throughout life. Clu-GFP expression clearly segregates a novel age-associated HSC subset that overlaps with but is distinct from those previously identified using antibodies against aging-associated proteins or reporter systems of aged HSC signature genes.
Clu-positive (Clu+) HSCs emerge as a minor population in the fetus and progressively expand with age. Clu+ HSCs display not only an increased propensity for myeloid/platelet-biased differentiation but also a unique behaviour in the BM, favouring self-renewal over differentiation into downstream progenitors. In contrast, Clu-negative (Clu-) HSCs exhibit lineage-balanced differentiation, which predominates in the HSC pool during development but becomes underrepresented as aging progresses. Both subsets maintain long-term self-renewal capabilities even in aged mice but contribute differently to hematopoiesis.
The predominant expansion of Clu+ HSCs largely drives the age-related changes observed in the HSC pool. Conversely, Clu- HSCs preserve youthful functionality and molecular characteristics into old age. Consequently, progressive changes in the balance between Clu+ and Clu- HSC subsets account for HSC aging. Our findings establish Clu as a novel marker for identifying aging-associated changes in HSCs and provide a new approach that enables lifelong tracking of the HSC aging process.
Link: https://doi.org/10.1...lood.2024025776
View the full article at FightAging
