Simulating mouse mammary gland development: cell ageing and its relation to stem and progenitor activity

Abstract. Background : Somatic stem and progenitor cell division is likely to be an important determinant of tumor development. Each division is accompanied by a risk of fixing genetic mutations, and/or generating innately immortal cells that escape normal physiological controls. Aim : Using biological information, we aimed to devise a theoretical model for mammary gland development that described the effect of various stem/progenitor cells activities on the demographics of adult mammary epithelial cell populations. Results : We found that mammary ductal trees should develop in juvenile mice despite widely variant levels of activity in the progenitor compartment. Sequestration (inactivation) of progenitor cells dramatically affected the aging-maturation of the population without affecting the total regenerative capacity of the gland. Our results showed that if stem and progenitor cells can be demonstrated in glands regenerated by serial transplantation, they originated in a canonical primary stem cell (providing a functional definition of mammary stem cells). Finally, when the probability of symmetric division of stem cells increased above a threshold, the mammary epithelial population overall was immortal during serial transplantation. Conclusions : This model provides, (1) a theoretical framework for testing whether the phenotypes of genetically modified mice (many of which are breast cancer models) derive from changes of stem and progenitor activity, and (2) a means to evaluate the resolving power of functional assays of regenerative capacity in mammary epithelial cell populations