Comparative mapping of crawling-cell morphodynamics in deep learning-based feature space

Author summary Migratory cells that move by crawling do so by extending and retracting their plasma membrane. When and where these events take place determine the cell shape, and this is directly linked to the movement patterns. Understanding how the highly plastic and interconvertible morphologies appear from their underlying dynamics remains a challenge partly because their inherent complexity makes quantitatively comparison against the outputs of mathematical models difficult. To this end, we employed machine-learning based classification to extract features that characterize the basic migrating morphologies. The obtained features were then used to compare real cell data with outputs of a conceptual model that we introduced which describes coupling via feedback between local protrusive dynamics and polarity. The feature mapping showed that the model successfully recapitulates the shape dynamics that were not covered by previous related models and also hints at the critical parameters underlying state transitions. The ability of the present approach to compare model outputs with real cell data systematically and objectively is important as it allows outputs of future mathematical models to be quantitatively tested in an accessible and common reference frame. Navigation of fast migrating cells such as amoeba Dictyostelium and immune cells are tightly associated with their morphologies that range from steady polarized forms that support high directionality to those more complex and variable when making frequent turns. Model simulations are essential for quantitative understanding of these features and their origins, however systematic comparisons with real data are underdeveloped. Here, by employing deep-learning-based feature extraction combined with phase-field modeling framework, we show that a low dimensional feature space for 2D migrating cell morphologies obtained from the shape stereotype of keratocytes, Dictyostelium and neutrophils can be fully mapped by an interlinked signaling network of cell-polarization and protrusion dynamics. Our analysis links the data-driven shape analysis to the underlying causalities by identifying key parameters critical for migratory morphologies both normal and aberrant under genetic and pharmacological perturbations. The results underscore the importance of deciphering self-organizing states and their interplay when characterizing morphological phenotypes.