Abstract

Studies in hematopoietic aging have shown that classically defined, highly purified hematopoietic stem cells (HSCs) increase in number but have impaired function and exhibit myeloid skewing. However, we identified a cycling population of HSCs in young mice that appear to be preferentially lost during standard HSC isolations and therefore poorly represented within the purified HSC population. Here, we sought to determine how aging may alter this total HSC population in unseparated murine whole bone marrow (WBM). In limit dilution competitive bone marrow transplantation, we found that, at 6 months post-transplant, old (24-26-mo-old) WBM had a 4-fold increase in functional HSCs compared to young (6-8-wk-old) WBM. Unlike purified old HSCs, old WBM showed only minimal myeloid skewing (myeloid: 26%±11% of old donor peripheral blood vs.19%±16% of young donor peripheral blood; average percent donor peripheral blood ± SD; n=26 mice). Interestingly, in two experiments, old WBM retained full engraftment capacity in secondary transplant with no myeloid skewing, while in a third experiment, old WBM engraftment was significantly decreased when compared to young WBM (15%±9% vs. 57%±3%, respectively; average% donor chimerism ± SD), and exhibited clear myeloid skewing (myeloid: 65%±7% of old donor peripheral blood vs. 20%±10% of young donor peripheral blood; 4-5mice/grp/exp). These data suggest that only those old HSCs in unseparated WBM with high engraftment capacity may retain youthful myeloid/lymphoid ratio patterns. Preliminary data in female mice were similar, showing that HSCs were 7.8-fold increased in old vs. young WBM, retained repopulation capacity in secondary transplantation, and displayed no significant myeloid skewing. These patterns of robust reconstitution without myeloid skewing by old WBM are quite distinct from those of the classically-defined, purified old HSCs, suggesting the presence of a unique HSC population in WBM with differential susceptibility to aging. Further study of this population may yield novel insights into the effects of aging on HSC function and lineage fate decisions and facilitate innovative rejuvenation strategies.

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