Abstract

Age-related morbidity is associated with a decline in hematopoietic stem cell (HSC) function, but the mechanisms of HSC aging remain unclear. We performed heterochronic HSC transplants followed by quantitative analysis of cell reconstitution. While young HSCs outperformed old HSCs in young recipients, young HSCs unexpectedly failed to outcompete the old HSCs of aged recipients. Interestingly, despite substantial enrichment of megakaryocyte progenitors (MkPs) in old mice in situ and reported platelet (Plt) priming with age, transplanted old HSCs were deficient in reconstitution of all lineages, including MkPs and Plts. We therefore performed functional analysis of young and old MkPs. Surprisingly, old MkPs displayed unmistakably greater regenerative capacity compared to young MkPs. Transcriptome analysis revealed putative molecular regulators of old MkP expansion. Collectively, these data demonstrated that aging affects HSCs and megakaryopoiesis in fundamentally different ways: whereas old HSCs functionally decline, MkPs gain expansion capacity upon aging. HIGHLIGHTSO_LIFrequencies and total cell numbers of HSCs and MkPs were increased upon aging C_LIO_LIReconstitution deficit by old HSCs was observed by chimerism and absolute cell numbers C_LIO_LIYoung HSCs did not have competitive advantage over old HSCs in aged recipient mice C_LIO_LIOld MkPs display remarkable capacity to engraft, expand, and reconstitute platelets C_LIO_LIAging is associated with changes in MkP genome-wide expression signatures C_LI