Article

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

Stem Cell and Regenerative Medicine Program, The Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
PLoS Computational Biology (Impact Factor: 4.83). 04/2013; 9(4):e1003006. DOI: 10.1371/journal.pcbi.1003006
Source: PubMed

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.

0 Followers
 · 
94 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The application of ex vivo synthetic DNA as a high capacity information storage medium is well documented. Herein, we consider the potential for synthetic DNA to be incorporated as part of the human genome; providing a definitive, accessible, in vivo database of patient history.
    04/2013; 4(2). DOI:10.4161/adna.25489

Full-text (2 Sources)

Download
40 Downloads
Available from
May 20, 2014