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: Our data show that upon activation, LT-HSCs are delayed in their quiescence exit. Because LT-HSCs have been estimated to divide very infrequently, approximately once every 135 and 280 days in mouse and human, respectively (Catlin et al., 2011; Wilson et al., 2008), we sought to quantify consequences of this delay to cell cycle entry in homeostatic conditions. Because it is impossible to experimentally examine homeostatic human HSC pool dynamics over long periods, we turned to computational modeling. Our data strongly suggest that control of cell division is achieved through regulation of quiescence exit and cell cycle transit as two discrete steps. We established an agent-based model to investigate (1) the consequences of independent control of the duration of quiescence exit and (2) the effect of the 5.8 hr delay in LT-HSC quiescence exit. In this model, the maintenance of the number of cells in the system is controlled in a closed loop, and dynamic properties of the model—how often cells divide and how quick the response to injury—arise purely from the different durations of the stages of cell division (Figure S6A). All parameters and assumptions of the model are reported in the Supplemental Experimental Procedures. Most parameters, in particular the division times (mean ± SD), were measured experimentally. When not possible (i.e., HSC pool exit rate and noise), we tested the full range of possible values (discussed in the Supplemental Experimental Procedures) and chose those predicting a number of HSC divisions per year that is in the range reported in the literature for human HSCs (Catlin et al., 2011) (Figures S6B–S6G). With this set of physiologically relevant parameters, we investigated the outcome of (1) a control situation in which division is controlled with one kinetic parameter (from reception of signal to the generation of two daughter cells, with cells committed to divide upon sensing the signal), and (2) a situation in which quiescence exit and cell cycle transit are controlled independently, and where commitment to division happens only once the cell has transitioned out of the quiescence exit phase (Figure 6A). We invariably found that the number of LT-HSC divisions is lower when the duration of a cell division starting from G0 is defined by two independent kinetic parameters (quiescence exit and cell cycle transit) rather than a single parameter describing the average division time (Figures 6B and 6C). Furthermore, the overall number of LT-HSC divisions simulated to occur over 1 year was again decreased with a 5.8 hr delay in LT-HSC tG0 exit (Figures 6B and 6C). In fact, a delay as short as 2.6 hr was sufficient to significantly spare the number of LT-HSC divisions (Figure 6D). In addition, in response to perturbation such as might be experienced under hematopoietic stress, the rate of recovery in the HSC and progenitor pools was considerably improved by regulation through two kinetic parameters and even further when the delay in tG0 exit in LT-HSCs was included (Figures 6E, S6H, and S6I). Our model thus demonstrates that the ability to modulate the length of G0 exit independently of changes in duration of cell cycle transit provides better robustness to homeostatic and stress response hematopoiesis. Importantly, a delay in the duration of G0 exit in LT-HSCs compared to ST-HSCs leads to further optimization, indicating that regulation of the duration of the G0 exit phase rather than that of a whole division is key to controlling HSC pool maintenance and hematopoietic system responses.
Affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada. Electronic address: email@example.com.