Experimental and computational modelling of collective cell migration in peripheral nerve repair

A number of biological processes, such as embryonic development, cancer invasion and wound repair, rely on collective cell migration, a process of cells migrate together in sheets, strands or clusters. Peripheral nerves have a remarkable ability to regenerate and re-establish function after injury. Our lab has previously shown that this process depends on the collective migration of Schwann cell cords into the wound, which guide regrowing axons across the injury site to promote re-innervation. Cell-cell contact dependent signalling between Schwann cells and wound fibroblasts plays a critical role in this process by promoting cord formation and directional migration through Eph/ephrin-dependent cell sorting. However, how the interplay of homotypic and heterotypic cell-cell interactions regulates the coherent collective migration of Schwann cells or which molecular are effectors involved is not fully understood. We combine cell and molecular biology experiments with computational simulations to develop a novel computational model of peripheral nerve repair which simulates the interactions between Schwann cells and fibroblasts at the wound site. First, using methods from statistical physics we analyse experimental \emph{in vitro} data to parametrize our model. Then, we use the model to explore the theoretical requirements for an emerging coordination (i.e. formation of collectively migrating Schwann cell cords) in the system in order to better understand the mechanisms by which peripheral nerve repair occurs.Open Acces

Direct cell–cell contact with the vascular niche maintains quiescent neural stem cells

The vasculature is a prominent component of the subventricular zone neural stem cell niche. Although quiescent neural stem cells physically contact blood vessels at specialised endfeet, the significance of this interaction is not understood. In contrast, it is well established that vasculature-secreted soluble factors promote lineage progression of committed progenitors. Here we specifically investigated the role of cell-cell contact-dependent signalling in the vascular niche. Unexpectedly, we find that direct cell-cell interactions with endothelial cells enforces quiescence and promotes stem cell identity. Mechanistically, endothelial ephrinB2 and Jagged1 mediate these effects by suppressing cell-cycle entry downstream of mitogens and inducing stemness genes to jointly inhibit differentiation. In vivo, endothelial-specific ablation of either of the genes which encode these proteins, Efnb2 and Jag1 respectively, aberrantly activates quiescent stem cells, resulting in depletion. Thus, we identify the vasculature as a critical niche compartment for stem cell maintenance, furthering our understanding of how anchorage to the niche maintains stem cells within a pro-differentiative microenvironment