Journal
STEM CELL REPORTS
Volume 16, Issue 6, Pages 1598-1613Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2021.04.016
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Funding
- NIH NIA Award [R01AG062879]
- NIH IMSD Training Grant [2R25GM05890318]
- Howard Hughes Medical Institute Gilliam Fellowship Award
- American Heart Association
- NIH NHLBI F31 Fellowship Award
- TobaccoRelated Disease Research Program Predoctoral Fellowship Award
- CIRM Shared Stem Cell Facilities [CL1-00506]
- CIRM Major Facilities [FA1-00617-1]
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This study revealed that aging affects hematopoietic stem cells (HSCs) and megakaryopoiesis in fundamentally different ways: while old HSCs functionally decline, megakaryocyte progenitors (MkPs) gain expansion capacity upon aging.
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. Although 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 with 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.
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