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

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.