We investigate the in vivo patterns of stem cell divisions in the human hematopoietic system throughout life. In particular, we analyze the shape of telomere length distributions underlying stem cell behavior within individuals. Our mathematical model shows that these distributions contain a fingerprint of the progressive telomere loss and the fraction of symmetric cell proliferations. Our predictions are tested against measured telomere length distributions in humans across all ages, collected from lymphocyte and granulocyte sorted telomere length data of 356 healthy individuals, including 47 cord blood and 28 bone marrow samples. We find an increasing stem cell pool during childhood and adolescence and an approximately maintained stem cell population in adults. Furthermore, our method is able to detect individual differences from a single tissue sample, i.e. a single snapshot. Prospectively, this allows us to compare cell proliferation between individuals and identify abnormal stem cell dynamics, which affects the risk of stem cell related diseases.
Human subjects: All samples and the approval for publication were taken with informed consent of all patients at the University Hospital Aachen according to the guidelines and the approval of the ethics committees at the University Hospital Aachen.
- Frank Jülicher, Max Planck Institute for the Physics of Complex Systems, Germany
© 2015, Werner et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
As an organism ages, its health-state is determined by a balance between the processes of damage and repair. Measuring these processes requires longitudinal data. We extract damage and repair transition rates from repeated observations of binary health attributes in mice and humans to explore robustness and resilience, which respectively represent resisting or recovering from damage. We assess differences in robustness and resilience using changes in damage rates and repair rates of binary health attributes. We find a conserved decline with age in robustness and resilience in mice and humans, implying that both contribute to worsening aging health – as assessed by the frailty index (FI). A decline in robustness, however, has a greater effect than a decline in resilience on the accelerated increase of the FI with age, and a greater association with reduced survival. We also find that deficits are damaged and repaired over a wide range of timescales ranging from the shortest measurement scales toward organismal lifetime timescales. We explore the effect of systemic interventions that have been shown to improve health, including the angiotensin-converting enzyme inhibitor enalapril and voluntary exercise for mice. We have also explored the correlations with household wealth for humans. We find that these interventions and factors affect both damage and repair rates, and hence robustness and resilience, in age and sex-dependent manners.
Intracellular states probed by gene expression profiles and metabolic activities are intrinsically noisy, causing phenotypic variations among cellular lineages. Understanding the adaptive and evolutionary roles of such variations requires clarifying their linkage to population growth rates. Extending a cell lineage statistics framework, here we show that a population’s growth rate can be expanded by the cumulants of a fitness landscape that characterize how fitness distributes in a population. The expansion enables quantifying the contribution of each cumulant, such as variance and skewness, to population growth. We introduce a function that contains all the essential information of cell lineage statistics, including mean lineage fitness and selection strength. We reveal a relation between fitness heterogeneity and population growth rate response to perturbation. We apply the framework to experimental cell lineage data from bacteria to mammalian cells, revealing distinct levels of growth rate gain from fitness heterogeneity across environments and organisms. Furthermore, third or higher order cumulants’ contributions are negligible under constant growth conditions but could be significant in regrowing processes from growth-arrested conditions. We identify cellular populations in which selection leads to an increase of fitness variance among lineages in retrospective statistics compared to chronological statistics. The framework assumes no particular growth models or environmental conditions, and is thus applicable to various biological phenomena for which phenotypic heterogeneity and cellular proliferation are important.