Robustness of differentiation cascades with symmetric stem cell division

Abstract

Stem cells (SCs) perform the task of maintaining tissue homeostasis by both self-renewal and differentiation. While it has been argued that SCs divide asymmetrically, there is also evidence that SCs undergo symmetric division. Symmetric SC division has been speculated to be key for expanding cell numbers in development and regeneration after injury. However, it might lead to uncontrolled growth and malignancies such as cancer. In order to explore the role of symmetric SC division, we propose a mathematical model of the effect of symmetric SC division on the robustness of a population regulated by a serial differentiation cascade and we show that this may lead to extinction of such population. We examine how the extinction likelihood depends on defining characteristics of the population such as the number of intermediate cell compartments. We show that longer differentiation cascades are more prone to extinction than systems with less intermediate compartments. Furthermore, we have analysed the possibility of mixed symmetric and asymmetric cell division against invasions by mutant invaders in order to find optimal architecture. Our results show that more robust populations are those with unfrequent symmetric behaviour.