UCLA

Lymphocyte development declines with age, which in turn contributes to the reduced replenishment of na�ve 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), myeloid biased (My-HSCs) and balanced (Bal-HSCs) hematopoietic 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. However, findings from this thesis show that this model needs to be revised. In particular, Ly-HSCs do no decline and increase significantly during aging. The lymphoid potential of old Ly-HSCs is similar to young Ly-HSCs ex vivo shown by the number and aging marker expression of produced lymphoid cells. But the genomic pattern of old Ly-HSCs turns into a myeloid biased pattern indicated by RNA-Sequencing results, which correlates with altered myeloid production from old Ly-HSCs. In terms of reduced lymphoid development in vivo during aging, the fact that elevated level of pro inflammatory cytokines, one character of senescence-associated secretory phenotype, was detected to significantly and irreversibly prohibit the lymphoid differentiation from Ly-HSCs. Based on the above results, we propose the revised aging model of hematopoietic stem cells: Ly-HSCs do not decline during aging; their lymphoid potential remains similar to young Ly-HSCs ex vivo, but when being under the pro inflammatory cytokines, their differentiation is irreversible blocked; Whereas, their myeloid production is altered even removing from proinflammatory condition, which correlates with the fact that old Ly-HSCs show myeloid-biased transcriptional pattern. Throughout the projects, the methods utilized include cells staining, flow cytometry, cell sorting, lymphoid and myeloid assays, HSC-OP9 co-culture, cell transplantation, qPCR and RNA-Sequencing. Two supplementary files were also included separately: Table 2-11 “Ly-HSC and My-HSC gene expression estimates and differential expression results” and Table 2-12 “Ly-HSC and My-HSC gene signature analysis and functional enrichment results”.