Abstract
SummaryAging is linked to functional deterioration and hematological diseases. The hematopoietic system is maintained by hematopoietic stem cells (HSCs), and dysfunction within the HSC compartment is thought to be a key mechanism underlying age-related hematopoietic perturbations. Using single-cell transplantation assays with five blood-lineage analysis, we previously identified myeloid-restricted repopulating progenitors (MyRPs) within the phenotypic HSC compartment in young mice. Here, we determined the age-related functional changes to the HSC compartment using over 400 single-cell transplantation assays. Notably, MyRP frequency increased dramatically with age, while multipotent HSCs expanded modestly within the bone marrow. We also identified a subset of functional cells that were myeloid restricted in primary recipients but displayed multipotent (five blood-lineage) output in secondary recipients. We have termed this cell type latent-HSCs, which appear exclusive to the aged HSC compartment. These results question the traditional dogma of HSC aging and our current approaches to assay and define HSCs.
Highlights
Long-term functionally multipotent mouse hematopoietic stem cells (HSCs), as defined by engraftment following primary and secondary transplantation, are found within a phenotypic CD34À/lowFlt3Àc-Kit+Sca-1+LineageÀ (CD34ÀKSL) bone marrow (BM) cell population (Osawa et al, 1996)
Using clonal analysis in combination with five-blood lineage analysis, we previously determined the functional heterogeneity of the phenotypic HSC compartment in young mice (Yamamoto et al, 2013)
Aging Is Associated with Altered Functional HSC Composition and an Expanded myeloid-restricted repopulating progenitors (MyRPs) Population To directly compare HSC heterogeneity during aging, it was first important to define phenotypic HSC (pHSC) regardless of age
Summary
Long-term functionally multipotent mouse hematopoietic stem cells (HSCs), as defined by engraftment following primary and secondary transplantation, are found within a phenotypic CD34À/lowFlt3Àc-Kit+Sca-1+LineageÀ (CD34ÀKSL) bone marrow (BM) cell population (Osawa et al, 1996). Even the most phenotypically ‘‘pure’’ HSC population remains functionally heterogeneous in terms of lineage output and self-renewal capacity (Wilson et al, 2015). Using clonal analysis in combination with five-blood lineage (nm, B, T, E and P) analysis, we previously determined the functional heterogeneity of the phenotypic HSC (pHSC) compartment in young mice (Yamamoto et al, 2013). Using paired-daughter cell analysis, we further demonstrated MyRPs could be directly generated from HSCs via a myeloid-bypass pathway through a single-cell division event
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