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      Lifespan Differences in Hematopoietic Stem Cells are Due to Imperfect Repair and Unstable Mean-Reversion

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          The life-long supply of blood cells depends on the long-term function of hematopoietic stem cells (HSCs). HSCs are functionally defined by their multi-potency and self-renewal capacity. Because of their self-renewal capacity, HSCs were thought to have indefinite lifespans. However, there is increasing evidence that genetically identical HSCs differ in lifespan and that the lifespan of a HSC is predetermined and HSC-intrinsic. Lifespan is here defined as the time a HSC gives rise to all mature blood cells. This raises the intriguing question: what controls the lifespan of HSCs within the same animal, exposed to the same environment? We present here a new model based on reliability theory to account for the diversity of lifespans of HSCs. Using clonal repopulation experiments and computational-mathematical modeling, we tested how small-scale, molecular level, failures are dissipated at the HSC population level. We found that the best fit of the experimental data is provided by a model, where the repopulation failure kinetics of each HSC are largely anti-persistent, or mean-reverting, processes. Thus, failure rates repeatedly increase during population-wide division events and are counteracted and decreased by repair processes. In the long-run, a crossover from anti-persistent to persistent behavior occurs. The cross-over is due to a slow increase in the mean failure rate of self-renewal and leads to rapid clonal extinction. This suggests that the repair capacity of HSCs is self-limiting. Furthermore, we show that the lifespan of each HSC depends on the amplitudes and frequencies of fluctuations in the failure rate kinetics. Shorter and longer lived HSCs differ significantly in their pre-programmed ability to dissipate perturbations. A likely interpretation of these findings is that the lifespan of HSCs is determined by preprogrammed differences in repair capacity.

          Author Summary

          All hematopoietic stem cells (HSCs) are characterized by the capacities to produce all blood cell-types by differentiation and to maintain their own population through self-renewal divisions. Every individual HSC, therefore, can generate a complete blood system, or clone, conveying oxygenation and immune protection for a limited time. The time for which all mature blood cell-types can be found in a clone is called the lifespan. Interestingly, HSCs with different lifespans co-exist in the same host. We address the unresolved question: what controls the lifespan of HSCs of the same genotype exposed to the same environment? Here, we use a new approach to multi-scale modeling based on reliability theory and non-linear dynamics to address this question. Large-scale fluctuations in the experimental failure rate kinetics of HSC clones are identified to predict small-scale, genome level, events of deep penetrance, or magnitudes that approach population size. We broadly find that one condition explains our experimental data: repair mechanisms are a priori imperfect and do not improve, nor deteriorate, during the lifespan. As a result, progressively “worse-than-old” genome replicates are generated in self-renewal. A likely interpretation of our findings is that the lifespan of adult HSCs is determined by epigenetically pre-programmed differences in repair capacity.

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          Most cited references 53

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          The serial cultivation of human diploid cell strains.

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            Oxidative stress shortens telomeres.

            Telomeres in most human cells shorten with each round of DNA replication, because they lack the enzyme telomerase. This is not, however, the only determinant of the rate of loss of telomeric DNA. Oxidative damage is repaired less well in telomeric DNA than elsewhere in the chromosome, and oxidative stress accelerates telomere loss, whereas antioxidants decelerate it. I suggest here that oxidative stress is an important modulator of telomere loss and that telomere-driven replicative senescence is primarily a stress response. This might have evolved to block the growth of cells that have been exposed to a high risk of mutation.
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              Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.

              Bone marrow hematopoietic stem cells (HSCs) are crucial to maintain lifelong production of all blood cells. Although HSCs divide infrequently, it is thought that the entire HSC pool turns over every few weeks, suggesting that HSCs regularly enter and exit cell cycle. Here, we combine flow cytometry with label-retaining assays (BrdU and histone H2B-GFP) to identify a population of dormant mouse HSCs (d-HSCs) within the lin(-)Sca1+cKit+CD150+CD48(-)CD34(-) population. Computational modeling suggests that d-HSCs divide about every 145 days, or five times per lifetime. d-HSCs harbor the vast majority of multilineage long-term self-renewal activity. While they form a silent reservoir of the most potent HSCs during homeostasis, they are efficiently activated to self-renew in response to bone marrow injury or G-CSF stimulation. After re-establishment of homeostasis, activated HSCs return to dormancy, suggesting that HSCs are not stochastically entering the cell cycle but reversibly switch from dormancy to self-renewal under conditions of hematopoietic stress.

                Author and article information

                Role: Editor
                PLoS Comput Biol
                PLoS Comput. Biol
                PLoS Computational Biology
                Public Library of Science (San Francisco, USA )
                April 2013
                April 2013
                18 April 2013
                : 9
                : 4
                Stem Cell and Regenerative Medicine Program, The Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America
                University of Notre Dame, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CEMS. Performed the experiments: GC. Analyzed the data: HBS. Wrote the paper: HBS CEMS.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Pages: 15
                This work was supported by the National Institutes of Health grants DDK48015 and AG023197 to CEMS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Computational Biology
                Population Modeling
                Developmental Biology
                Stem Cells
                Adult Stem Cells
                Hematopoietic Stem Cells
                Pattern Formation
                Systems Biology
                Nonlinear Dynamics
                Bone Marrow and Stem Cell Transplantation

                Quantitative & Systems biology


                This computational biology paper addresses the question of how adult hematopoietic stem cells age. It postulates that DNA repair mechanisms inside cells are imperfect, which then accounts for a slow accumulation of defects during the repeated cycles of self-renewal throughout the life span. Minute differences in repair efficiency among individual cells lead to a broad impact on their clonogenic expansion and survival. Thus, the individual cell-intrinsic DNA repair proficiency determines the lifespan and ageing of hematopoietic stem cells.

                2015-06-25 08:58 UTC

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