LAUSR

Our goal is to define the cellular and molecular mechanisms that control aging of the hematopoietic system. Given the increasing global life expectancy of people and the prevalence of age-related hematological diseases, understanding alterations to stem and progenitor cell function during aging is critical for developing preventative and restorative therapies. Previous reports have suggested that age-related morbidity is determined by functional decline of hematopoietic stem cells (HSCs). While HSCs themselves have been associated with hematopoietic aging, the role of progenitor cells during aging remains a mystery. Progenitor cells carry varied capacity to proliferate and differentiate in order to meet the demands of the blood system. Therefore, we hypothesize that progenitor cells play a significant role in the homeostatic decline associated with aging. Indeed, Megakaryocyte Progenitors (MkPs) have been shown to be consistently enriched in the aging bone marrow. Therefore, we specifically tackled the question – how might aging alter the functional and molecular regulation of MkPs? Surprisingly, and in stark contrast to the functional decline of aging HSCs, we found that old MkPs displayed greater capacity to generate platelets compared to young MkPs. These functional differences were apparent by both in vivo reconstitution and in vitro proliferation assays. To gain further insight into the changes in molecular regulation of MkP populations, we performed RNA sequencing (RNA-seq) analysis of young and old MkPs. Interestingly, their functional differences are paralleled by unique molecular regulators of old MkPs. These data demonstrate that megakaryopoiesis and MkP maintenance is fundamentally different between young and old mice, and that old MkPs gain expansion capacity whereas old HSCs functionally decline. Understanding these cellular and molecular events provides a promise for development of effective therapeutic strategies aimed at guiding differentiation and maturation toward a more youthful megakaryopoiesis.