Investigating the heterogeneous aging of individual hematopoietic stem cell clones

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Project Summary: Stem cells continuously replenish tissues and organs over the lifetime of an organism through their special capacity for self-renewal and differentiation. The prolonged life span of stem cell clones results in the accumulation of cellular and molecular damage. The resulting functional changes to stem cells over time underlie many age-related problems. For example, age-dependent decline in B- and T-cell production originates at the stem cell level and is responsible for immune problems among the elderly. In addition, leukemia in children predominantly involves lymphoid lineages, while leukemia in the elderly is largely myeloid in origin. This difference correlates with age-dependent changes in hematopoietic stem cell (HSC) differentiation from lymphoid bias to myeloid bias at the population level. It has recently become clear that individual HSCs do not age at the same rate. Studies from my lab and others suggest that equally aged HSCs exhibit different levels of myeloid bias within a single organism. The clonal expansion of individual HSCs can also vary so widely that a few HSC clones are found to supply the entire blood pool of elderly individuals. These observations indicate that individual stem cells of the same calendar age within the same organism acquire different aging phenotypes. The proposed research aims to determine the mechanisms underlying the heterogeneity of HSC aging phenotypes. We have developed a suite of cutting-edge tools to address this question at the single cell level. We have collected preliminary data suggesting that the distinct aging phenotypes of individual HSCs are regulated at the clonal level. In the proposed research, we will investigate the cellular and molecular mechanisms underlying the heterogeneous aging phenotypes of individual HSCs. Our research may identify new aging regulatory factors that are undetectable at the population level. Completion of our proposed research will provide many immediate clinical benefits. Our findings will advance the understanding of the pathogenesis of many age-related blood and immune diseases, including bone marrow failure, myeloproliferative disorders, and myelodysplastic syndromes. We may also identify new regulatory genes that improve current therapy or develop new classes of therapies to treat these diseases. Our ultimate goal is to harness the mechanisms that underlie the differential aging of individual stem cells to improve quality of life for the elderly.