Research Project
7911057
DESCRIPTION (provided by applicant): Published studies and our preliminary data indicate that hematopoietic stem cells (HSCs) from aged animals generate less lymphoid progeny than young HSCs. This results in an overrepresentation of myeloid cells in the periphery. Understanding the mechanisms that cause HSCs from aged animals to generate progeny skewed to the myeloid lineage would open avenues to correct or prevent the age-related decline in lymphopoiesis. All important functions of HSCs, including self-renewal and commitment, are determined on the level of a single HSC. Thus, a mechanistic understanding of the function and composition of the aged HSC compartment requires an examination on the clonal level. We developed an efficient method for isolating clonally derived HSCs. The analysis of young HSC clones led to the discovery of a new type of HSC, called lineage dominant HSC. We found that lineage dominant HSCs: 1) contribute to all hematopoietic lineages, albeit with a noticeably skewed ratio; 2) can have extensive self-renewal capacity; 3) maintain lineage dominance stably through multiple rounds of transplantation; 4) can be either myeloid or lymphoid dominant. The data indicate that lineage dominant HSCs are a new type of HSC with distinct development potential. We now hypothesize that the increased production of myeloid cells from the aged HSC compartment is caused by an accumulation of myeloid dominant HSCs. The central hypothesis of this application is that "aging does not change the behavior of individual HSCs, rather aging changes the composition of the HSC compartment." To test this, we propose to extend the clonal approach to the analysis of the aged HSC compartment. We propose three specific aims: 1) Is dysregulation of lymphoid and myeloid cells in aging due to loss of heterogeneity in the aged HSC compartment? 2) Is the microenvironment or are HSC-intrinsic effects responsible for the aged behavior of HSC? 3) Do HSCs from aged animals and myeloid dominant HSCs generate reduced levels of T cell precursors.
