(30 lines of text) The goal of this research is to identify the mechanistic origins of a newly-discovered type of hematopoietic (blood- forming) stem cell (HSC), which we have named the latent-HSC. HSCs are defined by functional assays, the gold-standard being transplantation into an irradiated (bone marrow-compromised) recipient. HSCs have two key functional characteristics: (1) multipotency, readout from the regeneration of the lympho-myeloid blood system in the recipient; (2) self-renewal, readout by stable blood system reconstitution, with long-term HSC activity confirmed by serial transplantation. HSCs are thought to be responsible for life-long blood system homeostasis, through gradual differentiation into cell-amplifying lineage-restricted progenitors. However, aging is associated with blood system deterioration, most notably loss of lymphoid immune cell production and myeloid malignancies, with age-related HSC dysfunction proposed as a key underlying mechanism. In a recent clonal analysis of the aged mouse HSC compartment, we identified a functionally-novel type of HSC. We have termed this population ?latent-HSCs? because following primary transplantation, latent-HSCs display only myeloid-restricted output, but following serial transplantation display full multipotent lympho-myeloid output. My laboratory was only able to detect latent-HSCs because we have pioneered HSC analysis at five-blood lineage resolution. Traditionally, HSCs have only been defined by neutrophil/monocyte, T and B cell output, but ignored the two most abundant blood cell types, platelets and erythrocytes. Latent-HSCs often only display platelet/erythrocyte output in primary recipients, undetectable by traditional methods. Surprisingly, latent-HSCs are more frequent than long-term multipotent HSCs in the aged bone marrow, but have not been detected in young mice. Such a cell type that gains multipotency with age (and serial transplantation) is difficult to reconcile with current models of hematopoiesis. However, our findings suggest there may be a reservoir of latent lymphoid potential in the aged bone marrow. By developing approaches to activate latent-HSCs, we may identify therapeutic strategies to boost the immune system in the elderly and extend healthy aging. This exploratory R21 research project aims to identify the origin of latent-HSCs, to better understand the biological and translational relevance of this novel age-specific stem cell population. We will test three hypotheses: (1) that the latent-HSC phenotype could be a consequence of transplanting aged myeloid-restricted stem/progenitors into a ?rejuvenating? young recipient bone marrow; (2) that latent-HSCs could be generated from myeloid stem/progenitors by somatic mutations that lead to acquisition of lymphoid potential; and (3) that primary transplantation stress could be insufficient to induce multipotent differentiation of aged latent-HSCs. This new research avenue into the cellular mechanisms of HSC aging aims to identify strategies to ?rejuvenate? stem cell activity and prevent age-related loss of immune function. In summary, the study will set a new direction in stem cell aging research, and will lead to new models and assays in biomedical science.
(2-3 sentences) Multipotent hematopoietic (blood-forming) stem cells (HSCs) generate both myeloid and lymphoid cell types to sustain blood system homeostasis but are thought to lose lymphoid potential with age, compromising immune system function in the elderly. We have recently identified a functionally-novel type of HSC that is exclusive to the aged bone marrow, the ?latent-HSC?, which is myeloid-restricted until serial transplantation when it acquires multipotent lympho-myeloid capacity. By combining functional stem cell assays with cellular and genetic approaches we will characterize the origin of latent-HSCs, to re-define our current models of HSC aging and to identify therapeutic opportunities to rejuvenate the defective aged HSC compartment.