A study on the effects of the CCL5-CCR5 signaling axis on myeloid bias of aged hematopoietic stem cells

Hematopoietic stem cells (HSCs) are multipotent self-renewing cells that give rise to all types of blood cells. Past research has identified that long-term hematopoietic stem cells (LT- HSCs) in young mice and humans produce a balanced output of lymphoid and myeloid cells, while in old age they are largely replaced by myeloid biased HSCs (My-HSC). It has not yet been determined whether this transition results from epigenetic changes in a single population of HSC or if two or more subsets of HSCs exist that gain or lose dominance with age via processes of selection. Whether epigenetic change or competition, several characteristics of each may exist to ensure that the appropriate subset is placed in niches that support them. HSC can be mobilized into the blood and home selectively to target tissues. Chemokines are the class of molecules that determine intra- organ migration of HSCs to appropriate niches. Here, we show that the chemokine receptor CCR5 is mainly expressed on My-HSCs, and therefore the frequency of CCR5+ HSCs increases with age. Aged HSCs that do not express CCR5 generate lower frequency of myeloid cells than lymphoid cells upon transplantation into recipients. Additionally, disruption of the CCL5-CCR5 signaling axis with blocking antibodies results in higher frequency of naïve T cells and mature B cells in peripheral blood of aged mice, supporting research that shows the depletion of My-HSCs can result in the rejuvenation of adaptive immunity.