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

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  • Hans B Sieburg
  • Giulio Cattarossi
  • Christa E Muller-Sieburg

Abstract

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.

Suggested Citation

  • Hans B Sieburg & Giulio Cattarossi & Christa E Muller-Sieburg, 2013. "Lifespan Differences in Hematopoietic Stem Cells are Due to Imperfect Repair and Unstable Mean-Reversion," PLOS Computational Biology, Public Library of Science, vol. 9(4), pages 1-15, April.
  • Handle: RePEc:plo:pcbi00:1003006
    DOI: 10.1371/journal.pcbi.1003006
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    1. Derrick J. Rossi & David Bryder & Jun Seita & Andre Nussenzweig & Jan Hoeijmakers & Irving L. Weissman, 2007. "Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age," Nature, Nature, vol. 447(7145), pages 725-729, June.
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    5. Sánchez Granero, M.A. & Trinidad Segovia, J.E. & García Pérez, J., 2008. "Some comments on Hurst exponent and the long memory processes on capital markets," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 387(22), pages 5543-5551.
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    1. Lorand Gabriel Parajdi & Radu Precup & Eduard Alexandru Bonci & Ciprian Tomuleasa, 2020. "A Mathematical Model of the Transition from Normal Hematopoiesis to the Chronic and Accelerated-Acute Stages in Myeloid Leukemia," Mathematics, MDPI, vol. 8(3), pages 1-18, March.

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