Seminars

The role of tissue stiffness in controlling cell behaviours ranging from proliferation to signalling and activation is by now well accepted. A key focus of experimental studies into mechanotransduction are focal adhesions, localised patches of strong adhesion, where cell signalling has been established to occur. However, these adhesion sites themselves alter the mechanical equilibrium of the system determining the force balance and work done. To explore this I have developed an active matter continuum description of cellular contractility and will discuss recent results on the specific role of spatial positioning of adhesions in mechanotransduction. I show using energy arguments why the experimentally observed arrangements of focal adhesions develop and the implications this has for stiffness sensing and cellular contractility control. I will also show how adhesions play distinct roles in single cells and tissue layers respectively drawing on recent experimental work with Dr JR Davis (Manchester University) and Dr Nic Tapon (Crick Institute) with applications to epithelial layers and organoids.

In this talk I will discuss how phenotypic heterogeneity affects emergent pattern formation in living active matter with chemical communication between cells. In doing so, I will explore how the emergent dynamics of multicellular communities are qualitatively different in comparison to the dynamics of isolated or non-interacting cells. I will focus on two specific projects. First, I will show how genetic regulation of chemical communication affects motility-induced phase separation in cell populations. Second, I will demonstrate how chemotaxis along self-generated signal gradients affects cell populations undergoing 3D morphogenesis.

Morphogen protein gradients play an essential role in the spatial regulation of patterning during embryonic development.  The most commonly accepted mechanism of protein gradient formation involves the diffusion and degradation of morphogens from a localized source. Recently, an alternative mechanism has been proposed, which is based on cell-to-cell transport via thin, actin-rich cellular extensions known as cytonemes. It has been hypothesized that cytonemes find their targets via a random search process based on alternating periods of retraction and growth, perhaps mediated by some chemoattractant. This is an actin-based analog of the search-and-capture model of microtubules of the mitotic spindle searching for cytochrome binding sites (kinetochores) prior to separation of cytochrome pairs. In this talk, we introduce a search-and-capture model of cytoneme-based morphogenesis, in which nucleating cytonemes from a source cell dynamically grow and shrink until making contact with a target cell and delivering a burst of morphogen. We model the latter as a one-dimensional search process with stochastic resetting, finite returns times and refractory periods. We use a renewal method to calculate the splitting probabilities and conditional mean first passage times (MFPTs) for the cytoneme to be captured by a given target cell. We show how multiple rounds of search-and-capture, morphogen delivery, cytoneme retraction and nucleation events lead to the formation of a morphogen gradient. We proceed by formulating the morphogen bursting model as a queuing process, analogous to the study of translational bursting in gene networks. We end by briefly discussing current work on a model of cytoneme-mediated within-host viral spread.