GSE112769
Lymphoid Biased Hematopoietic Stem Cells are Maintained with Age and Retain Normal Developmental Potential in the Absence of Inflammatory Stimuli
The hematopoietic stem cell (HSC) compartment includes lymphoid biased (Ly-HSCs) and myeloid biased (My-HSCs) subsets. Current models propose that the number of Ly-HSCs declines with age and this contributes to the diminution of lymphopoiesis that is a feature of aging. This view is based on a reduction in the frequency of Ly-HSCs in old bone marrow, but we now show that when total HSCs are taken into account, the number of Ly-HSCs is not reduced in old mice. We further demonstrate that old Ly-HSCs exhibit a normal capacity to produce lymphoid progenitors when removed from the bone marrow. However, the production of inflammatory cytokines is known to increase with age, and when Ly-HSCs are exposed to these mediators, lymphocyte production is blocked. We also demonstrate that old Ly-HSCs generate myeloid cells that phenotypically resemble those produced by old My-HSCs, a finding consistent with the myeloid biased gene expression pattern of old Ly-HSCs. These observations indicate that current models of how aging impacts the lymphopoietic potential of HSCs need to be revised and point to changes in the in vivo environment, rather than intrinsic changes in HSCs, as the principal cause of the reduced lymphopoiesis and increased myelopoiesis during aging. Overall design: We isolated Ly-HSCs (lineage negative, Sca-1+ CD117(c-kit)+ CD48- CD135- CD150low) and My-HSCs (lineage negative, Sca-1+ CD117(c-kit)+ (LSK) CD48- CD135- CD150high) from three independent groups of young (8-12 week-old) and old (18 months) mice and performed RNA-Seq.