title: 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.
authors: Stem Cell and Regenerative Medicine Program, The Sanford-Burnham Medical Research Institute, La Jolla, California, USA. hsieburg@sanfordburnham.org
authors: Hans B
authors: HB
authors: Sieburg
authors: Giulio
authors: G
authors: Cattarossi
authors: Christa E
authors: CE
authors: Muller-Sieburg
mesh_terms: D000465:Algorithms; D000818:Animals; D001773:Blood Cells; D003198:Computer Simulation; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D016678:Genome; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011381:Programming Languages; D015203:Reproducibility of Results; D012984:Software
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