The self-renewing lymphoid-biased hematopoietic stem cells support long-term lymphopoiesis in mice

Lymphopoiesis is profoundly impaired during ageing largely due to ageing-susceptible changes of hematopoietic stem cells (HSCs). How to maximize the preservation of lymphopoiesis during ageing remains unknown and whether there exists a specific population with life-long lymphoid potential not intensively affected by ageing is of substantial scientific and translational significance. Here, we identified a self-renewable, lymphoid-biased hematopoietic stem cells (Ly-biased HSCs) subset within the EPCR+CD150 ⁻ CD48 ⁻ LSK (HSC2) population, phenotypically termed EPCR ⁺ MPP6 (CD34 ⁻ CD135 ⁻ HSC2), that not only displayed comparable multi-lineage potential with HSC in young mice, but also maintained similar lymphoid-biased reconstitution during aging. The lymphoid-biased characteristics of EPCR ⁺ MPP6 were also supported by immune associated program at transcriptome and proteomic levels. Notably, EPCR ⁺ MPP6 and HSCs rarely generated one another following the first cell division in vitro and under homeostasis in vivo indicating the most likely independent relationship between them and an earlier-than-thought bifurcation of the lymphoid differentiation pathway, which may function as a backup source to support lymphopoiesis. Collectively, this newly defined Ly-biased HSCs represent a promising cellular target for both mechanistic studies and therapeutic strategies concerning age-related immune decline.