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. 2009 Jul;5(7):e1000447.
doi: 10.1371/journal.pcbi.1000447. Epub 2009 Jul 24.

Stem Cell Proliferation and Quiescence--Two Sides of the Same Coin

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Free PMC article

Stem Cell Proliferation and Quiescence--Two Sides of the Same Coin

Ingmar Glauche et al. PLoS Comput Biol. .
Free PMC article

Abstract

The kinetics of label uptake and dilution in dividing stem cells, e.g., using Bromodeoxyuridine (BrdU) as a labeling substance, are a common way to assess the cellular turnover of all hematopoietic stem cells (HSCs) in vivo. The assumption that HSCs form a homogeneous population of cells which regularly undergo cell division has recently been challenged by new experimental results. For a consistent functional explanation of heterogeneity among HSCs, we propose a concept in which stem cells flexibly and reversibly adapt their cycling state according to systemic needs. Applying a mathematical model analysis, we demonstrate that different experimentally observed label dilution kinetics are consistently explained by the proposed model. The dynamically stabilized equilibrium between quiescent and activated cells leads to a biphasic label dilution kinetic in which an initial and pronounced decline of label retaining cells is attributed to faster turnover of activated cells, whereas a secondary, decelerated decline results from the slow turnover of quiescent cells. These results, which support our previous model prediction of a reversible activation/deactivation of HSCs, are also consistent with recent findings that use GFP-conjugated histones as a label instead of BrdU. Based on our findings we interpret HSC organization as an adaptive and regulated process in which the slow activation of quiescent cells and their possible return into quiescence after division are sufficient to explain the simultaneous occurrence of self-renewal and differentiation. Furthermore, we suggest an experimental strategy which is suited to demonstrate that the repopulation ability among the population of label retaining cells changes during the course of dilution.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Compartment models of stem cell organization.
A. The red boxed area indicates the population of HSCs. Each cell within this population undergoes cell division with rate s (generating two daughter cells), differentiation with rate d and cell death with rate c, shown by the arrows. The processes of differentiation and cell death lead to the removal of the cell from the HSC compartment. Upon label administration a certain fraction F0 of HSCs gets initially labeled. As N subsequent divisions are necessary to dilute the label below the detection threshold, this can be visualized by a sequence of N compartments named L1 to LN, shown in grey. Cells within theses boxes undergo cell division (transit from Li to Li+1), differentiation, and cell death with the same rates as non-labeled cells. After the Nth division the cells are no longer distinguishable from unlabeled HSCs. B. The population of HSCs is composed of two, subpopulations, indicated by the lower (light green) and upper (dark green) boxes, which differ in their specific rates for cell division (sf and ss), differentiation (df and ds) and cell death (cf and cs). Otherwise, the fast and the slow dividing subpopulations behave identical to the case illustrated in subfigure A. Labeled cells are present in both these subpopulations and need to undergo N subsequent divisions to dilute label below the detection threshold.
Figure 2
Figure 2. Kinetics of label dilution described in the context of compartment models.
A. The red and the green curves represent best fit scenarios for the data on BrdU label dilution obtained from Kiel et al. (black circles, mean+/−SD) . The red curve corresponds to the one compartment model (compare Figure 1A) in which N = 2 divisions are necessary to dilute the label below the detection threshold. The green curve corresponds to the two compartment model (cf. Figure 1B) with parameters formula image and formula image, also assuming N = 2 divisions until label dilution. B. The same compartment models are fitted to the data on BrdU label dilution obtained from Wilson et al. (black circles, mean values) , assuming that N = 5 divisions are necessary for label dilution. Although the one compartment model fails to describe the data (red curve), the two compartment model (green curve) captures the overall behavior for formula image and formula image.
Figure 3
Figure 3. Modeling concept of a self-organized HSC population.
A. The model setup is characterized by two different signal contexts (A and formula image). Cells can reversibly change between A and formula image depending on the cell numbers and the cell specific affinity a. Whereas activated cells in formula image undergo divisions and exponentially degrade their cell specific affinity a, cells in A are quiescent and preserve/regain their affinity a. Further details of the model are given in , and in the Supporting Information Text S1. The blue box indicates the region in which cells are considered as HSCs according to a certain purification procedure.
Figure 4
Figure 4. Kinetics of label dilution in the context of the single-cell based model.
A. Optimal fit of the single cell-based model (red curve, average of 100 simulation runs) to the particular data by Kiel et al. (black dots +/−SD). The corresponding green and blue curves show the corresponding fraction of activated and quiescent cells among the label retaining cells, respectively. F0 = 45% of HSCs are initially labeled, N = 2 divisions are necessary to dilute the label below the detection threshold. B. Corresponding fit for the data by Wilson et al. . F0 = 71% of HSCs are initially labeled, N = 5 divisions are necessary for label dilution. C. Distribution of individual turnover times in the simulation for activated (green) and quiescent cells (blue). D. Percentage of label retaining cells as a function of time, depending on the number of divisions N to dilute the label. Dark lines are the average values over 100 simulations, shaded regions indicate +−SD.
Figure 5
Figure 5. Engraftment levels as a function of time of dilution.
A. The average level of donor engraftment for the L+ (black) and L− cells (grey) is shown as a function of the time of dilution. Initially F0 = 71% of all HSCs are randomly labeled. At each time point of dilution 20 randomly chosen L+ or L− cells are transplanted competitively with 20 randomly selected HSC from the host system. Engraftment levels of the donor cells are assessed for the time point 10 weeks after transplantation. Simulation results are averages of 100 independent realizations +/−SD. B. Identical setup to subfigure A, only the labeling routine is restricted to the most primitive cells (F0 = 100% for cells with cell specific affinity a>0.9).

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