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 Blood, 15 December 2008, Vol. 112, No. 13, pp. 4874-4883.
Prepublished online as a Blood First Edition Paper on September 22, 2008; DOI 10.1182/blood-2008-05-155374.

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HEMATOPOIESIS AND STEM CELLS

Characterization and quantification of clonal heterogeneity among hematopoietic stem cells: a model-based approach

Ingo Roeder1,2, Katrin Horn1, Hans-Bernd Sieburg3, Rebecca Cho3, Christa Muller-Sieburg3, and Markus Loeffler1

1 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; 2 Department of Computing, Goldsmiths, University of London, London, United Kingdom; and 3 Sidney Kimmel Cancer Center, San Diego, CA

Hematopoietic stem cells (HSCs) show pronounced heterogeneity in self-renewal and differentiation behavior, which is reflected in their repopulation kinetics. Here, a single-cell–based mathematical model of HSC organization is used to examine the basis of HSC heterogeneity. Our modeling results, which are based on the analysis of limiting dilution competitive repopulation experiments in mice, demonstrate that small quantitative but clonally fixed differences of cellular properties are necessary and sufficient to account for the observed functional heterogeneity. The model predicts, and experimental data validate, that competitive pressures will amplify small clonal differences into large changes in the number of differentiated progeny. We further predict that the repertoire of HSC clones will evolve over time. Last, our results suggest that larger differences in cellular properties have to be assumed to account for genetically determined differences in HSC behavior as observed in different inbred mice strains. The model provides comprehensive systemic and quantitative insights into the clonal heterogeneity among HSCs with potential applications in predicting the behavior of malignant and/or genetically modified cells.


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