Unveiling Stem Cell Kinetics: Prime Time for Integrating Experimental and Computational Models

Abstract

experiments includ-ing stem cells or cancer stem cells areperformed at an increasing rate, produc-ing a wealth of exciting and sometimesunexpected, even puzzling data. Intuitivespeculation about underlying biologicalmechanisms often prevails as experimen-tal fishing expeditions are costly and timeconsuming. Based on first principles ofcell kinetics without assumptions aboutthe emerging population dynamics, quan-titative mathematical and computationalmodels are emerging as invaluable tools tocorrelate and rank the likelihood of cell-levelhypotheseswithpopulationlevelend-points. To fully utilize the power of quan-titative models, experimental and mod-eling approaches must be integrated anditeratively inform and validate each other.I read with great interest the articleby Tang et al. (1) and praise their iter-ative interdisciplinary approach to cor-relate mammary stem cell kinetics withthe elevated breast cancer risk after expo-sure to irradiation in young girls but notadult women. Experiments performed byTang et al. show that ionizing irradiationof pubertal mammary glands yields anincrease in mammary stem cells, prompt-ing questions about the underlying mecha-nisms. It has been previously observed thatirradiation increases the ratio of stem cellsin a population, which has been attrib-uted to better stem cell DNA damagerepair mechanisms (2–4). A recent com-putational model was able to show thatdecreased radiosensitivity alone is insuf-ficient to achieve the observed increasein stem cell ratio, and that a shift toincreased symmetric stem cell divisionmust occur especially during fractionatedexposure to irradiation (5). By consideringpre- and post-pubertal breast morpholo-gies, Tang et al. use agent-based models(ABMs) to simulate radiation responsesof juvenile and adult populations. Sur-prisingly, radiation-induced cell death didnot contribute to increased stem cell fre-quency independently of the dose deliv-ered. Instead the model revealed thatthe combination of increased self-renewaland cell proliferation in pubertal mam-mary glands led to stem cell enrichment.In contrast epithelial-mesenchymal transi-tion(EMT)wasshowntoincreasestemcellfrequency not only in pubertal mammaryglands but also in adult glands. This latterprediction, however, contradicted