Ibec Seminar: Pablo J. Sáez

Decision-making during cell migration

Moving cells navigate inside living tissues often encountering obstacles and junctions, where their path branches into alternative directions of migration. This is the case of cells moving on top or within blood vessels, which often bifurcate into branches. Cells have diverse migratory strategies that differentially rely on the adhesion to the substrate. Cells that undergo mesenchymal migration are highly dependent on the adhesion to the substrate, and when facing bifurcations are forced to coordinate the adhesion and detachment of the competing branches. Recent studies showed how the decision is made -to keep or retract a branch and choose a new direction- when there is bias: open versus dead-end, differences in pressure, presence/absence of a chemoattractant. However, much less is know about how cells decide a new direction when the decision is unbiased. Similarly, it is poorly understood how migrating cells coordinate membrane dynamics and polarity during branching to maintain a good trade-off between microenvironmental exploration and migratory efficiency.  Here, we use in vitro live-cell imaging using different levels of complexity, conventional and label-free microscopy (holotomography), advanced image analysis and in vivo live-cell imaging (zebrafish) to analyze the response of migrating cells when facing symmetric junctions, and extreme branching when cells simultaneously face several bifurcations. We found that actin and membrane dynamics play a key role to choose a new direction in both cases i) when cells face a single symmetric junction (Y-shaped with equal angles, Ron et al. 2024), and ii) when cells exhibit high levels of branching because they face several junctions at the same time (Liu et al.). In addition, we found that migrating immune cells have a fine tune regulation of branching in order to coordinate surveillance and migration. Microtubules, and organelle position and function were required in a cell-specific manner for efficient directional decision-making in symmetric, as well as in asymmetric junctions (i.e. different angles or adhesion). We integrated this data into a coarse-grain model to explain and predict migratory behaviour during decision-making. These results shed light on the mechanisms by which cells resolve unbiased junctions and branching during cell migration.