Control of epidermal stem cell clusters by Notch-mediated lateral induction

Stem cells in the basal layer of human interfollicular epidermis form clusters that can be reconstituted in vitro. In order to supply the interfollicular epidermis with differentiated cells, the size of these clusters must be controlled. Evidence suggests that control is regulated via differentiation of stem cells on the periphery of the clusters. Moreover, there is growing evidence that this regulation is mediated by the Notch signalling pathway. In this paper, we develop theoretical arguments, in conjunction with computer simulations of a model of the basal layer, to show that regulation of differentiation is the most likely mechanism for cluster control. In addition, we show that stem cells must adhere more strongly to each other than they do to differentiated cells. Developing our model further we show that lateral-induction, mediated by the Notch signalling pathway, is a natural mechanism for cluster control. It can not only indicate to cells the size of the cluster they are in and their position within it, but it can also control the cluster size. This can only be achieved by postulating a secondary, cluster wide, differentiation signal, and cells with high Delta expression being deaf to this signal.