Modeling mechanical control of spindle orientation of intestinal crypt stem cells

Abstract

Tissue development requires a control over the sequence of symmetric and asymmetric stem cell divisions to obtain the specific numbers of differentiated cells populating the tissue and stem cells residing in the niche. A good experimental model to study this process is the mouse intestinal crypt development, where it has been shown that stem cells follow an optimal strategy in which asymmetric division occurs only after all symmetric divisions have taken place to reach a fixed number of cells in the niche in the shortest time. Here we introduce a model of stem cell division that is able to explain the experimentally observed stem cell population dynamics by the effect of mechanical forces acting on the spindle. We also observe that the mechanically induced strategy for development is sub-optimal and crucially depends on the stiffness of the spindle. These findings highlight the crucial importance of mechanical forces for the development and maintenance of the intestinal crypt.