The Extrinsic Noise Effect on Lateral Inhibition Differentiation Waves

Abstract

Multipotent differentiation, where cells adopt one of several cell fates, is a determinate and orchestrated procedure that often incorporates stochastic mechanisms in order to diversify cell types. How these stochastic phenomena interact to govern cell fate is poorly understood. Nonetheless, cell fate decision-making procedure is mainly regulated through the activation of differentiation waves and associated signaling pathways. In the current work, we focus on the Notch/Delta signaling pathway, which is not only known to trigger such waves but also is used to achieve the principle of lateral inhibition (i.e., a competition for exclusive fates through cross-signaling between neighboring cells). Such a process ensures unambiguous stochastic decisions influenced by intrinsic noise sources, such as those found in the regulation of signaling pathways, and extrinsic stochastic fluctuations attributed to microenvironmental factors. However, the effect of intrinsic and extrinsic noise on cell fate determination is an open problem. Our goal is to elucidate how the induction of extrinsic noise affects cell fate specification in a lateral inhibition mechanism. Using a stochastic Cellular Automaton with continuous state space, we show that extrinsic noise results in the emergence of steady-state furrow patterns of cells in a “frustrated/transient” phenotypic state.