Lymphoid biased hematopoietic stem cells acquire a myeloid pattern of gene expression with age.

Abstract Lymphocyte development declines with age, which in turn contributes to the reduced replenishment of naïve lymphocytes in secondary lymphoid organs. An impaired ability of old hematopoietic stem cells (HSCs) to generate lymphoid progeny is thought to contribute to this attenuation of lymphopoiesis. It is now recognized that the HSC compartment is heterogeneous and includes lymphoid biased (Ly-HSCs) and myeloid biased (My-HSCs) stem cells. Previous studies have demonstrated that the frequency of Ly-HSCs is reduced with age, and this observation has resulted in the formulation of a model of stem cell aging which proposes that the age-related decline in lymphocyte development is due to a reduction in the number of these lymphoid biased precursors. We now show that when total HSC number is taken into account, Ly-HSCs do not decline in number with age and that compartment size is maintained in old mice. In order to obtain insights into why lymphocyte development is reduced with age, we compared the transcriptomes of young and old Ly-HSCs. We found that 371 genes were differentially expressed between young and old Ly-HSCs, and Gene Ontology analysis revealed that multiple processes that included regulation of apoptosis, chromatin remodeling, cytoskeleton organization, and cell cycle progression were altered by aging. We also transcriptionally profiled young and old My-HSCs and analysis of the data unexpectedly revealed that the transcriptomes of old Ly-HSCs resembled that of old My-HSCs. Based on these results, we propose a revised model of HSC aging in which altered patterns of gene expression that occur in aging Ly-HSCs, rather than a reduction in their number, contribute to declines in lymphocyte production in old individuals.