CDK6 levels regulate quiescence exit in human hematopoietic stem cells.
Bottom Line: Short-term (ST)-HSCs are also quiescent but contain high CDK6 protein levels that permit rapid cell cycle entry upon mitogenic stimulation.Enforced CDK6 expression in LT-HSCs shortens quiescence exit and confers competitive advantage without impacting function.Thus, differential expression of CDK6 underlies heterogeneity in stem cell quiescence states that functionally regulates this highly regenerative system.
Affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada. Electronic address: firstname.lastname@example.org.Show MeSH
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Mentions: The cycling properties of mouse HSC subpopulations are described, but they have not been validated in the human HSC hierarchy. Human LT-HSCs, isolated from umbilical cord blood (CB) as Lin− CD34+ CD38− CD45RA− CD90+ CD49f+ (Notta et al., 2011), provide robust multilineage repopulation beyond 30 weeks in the NSG mouse xenograft assay with about 10% frequency (Notta et al., 2011) and efficiently engraft upon secondary transplantation (Table S1). In contrast, Lin− CD34+ CD38− CD45RA− CD90− CD49f− cells generate multilineage grafts over intermediate time periods (Notta et al., 2011), but they lack serial transplantation ability and thus have limited self-renewal (Table S1). According to the criteria used in mouse, this population corresponds to ST-HSCs. Importantly, LT- and ST-HSC-enriched populations can be purified with the cell surface markers indicated above from NSG mice repopulated with human cells (Table S1). Similar to transplantation models in mice, phenotypic human LT- and ST-HSCs expand in the first 4 weeks after xenotransplant (with >50% that actively cycle) then regain quiescence by 20 weeks when a transient equilibrium phase is reached (Figures 1A, S1A, and S1B). In our model, functionally repopulating LT-HSCs expanded ≈30-fold in 20 weeks (Figure 1B).
Affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada. Electronic address: email@example.com.