Group Decisions Influence Emergence and Regulation of Leaders during Collective Migration of Epithelial Cells

Collective migration is a central event involving coordinated movement of several individuals. One of the critical events during collective migration is the emergence of leading individuals, who provide directional guidance for the group movement. While on the move, animals select their leaders by a collective decision making process, which require active participation of the followers. On the contrary, the prevalent view on collective cell migration, especially in the context of epithelial cells during wound healing, assumes a hierarchical leader-follower organization and belittles the contribution of follower cells in choosing or regulating the leaders. Furthermore, how the dynamics of cells located at the wound margin evolve as the wound heals, remains illusive. Here, we report and analyse distinct phases of collective migration during wound closure and demonstrate how cellular-level shared decision-making process and collective mechanical dynamics influence selection, regulation and kinematics of leader cells in these phases. We found that in the preparatory phase, before the initiation of migration (Phase 0), the selection of leader cells at the epithelial wound margin depends on the pre-migratory dynamics of the follower cells situated immediately behind the future leaders. Long before the prospective leaders actually start displaying their phenotypic peculiarities, cells behind them manifest stochastic augmentations in the traction forces and monolayer stresses, and display large perimeter-to-area ratio indicating a local unjamming in the followers much before the leaders are selected. Further, introducing an unjammed or fluidic follower at the back stimulates leader cell formation at the margin thereby indicating the role of collective bulk dynamics in leader cell selection. Interestingly, the length upto which cells cooperatively join forces, corresponds very well with the distance between the two emerging leaders and this mechano-biological control remains preserved even in the presence of geometric bias or physiological levels of chemical cue at the interface. Immediately after the initiation of migration (Phase 1), leaders show their distinct phenotypes and drive the cellular outgrowths. In this phase, pluricellular actin belt at the margin regulates the fraction of marginal leaders, which therefore remains unchanged, while the number of followers per leader increases with time. As the migration progresses, fraction of leader cells increases while the latter settles to a steady level set again by the length scale of cell-cell force transmission (Phase 2). Any perturbations in mechanical forces that modifies the force correlation lengths, invariably enforces a change in the number of followers per leader thereby modifying the time required to transit from one phase to the other. Furthermore, orientation of focal adhesions and persistence of cellular motions also display this phase specific behaviour. Together, these findings provide a novel system insight into collective cell migration and indicate integrative leader-follower interactions during wound closure. Given the physiological and pathological importance of leader cell formation in epithelial wound healing, in organogenesis and in metastatic migration of cancer cells, the system-view that the results offer here is anticipated to have to a long-standing impact on the design and discovery of avant-garde therapeutic strategies in future

Why does epithelia display heterogeneity?:Bridging physical and biological concepts

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Role of heterogeneity in dictating tumorigenesis in epithelial tissues

Abstract Biological systems across various length and time scales are noisy, including tissues. Why are biological tissues inherently chaotic? Does heterogeneity play a role in determining the physiology and pathology of tissues? How do physical and biochemical heterogeneity crosstalk to dictate tissue function? In this review, we begin with a brief primer on heterogeneity in biological tissues. Then, we take examples from recent literature indicating functional relevance of biochemical and physical heterogeneity and discuss the impact of heterogeneity on tissue function and pathology. We take specific examples from studies on epithelial tissues to discuss the potential role of inherent tissue heterogeneity in tumorigenesis

Mechanobiology of leader–follower dynamics in epithelial cell migration

Collective cell migration is fundamental to biological form and function. It is also relevant to the formation and repair of organs and to various pathological situations, including metastatic propagation of cancer. Technological, experimental, and computational advancements have allowed the researchers to explore various aspects of collective migration, spanning from biochemical signalling to inter-cellular force transduction. Here, we summarize our current understanding of the mechanobiology of collective cell migration, limiting to epithelial tissues. On the basis of recent studies, we describe how cells sense and respond to guidance signals to orchestrate various modes of migration and identify the determining factors dictating leader–follower interactions. We highlight how the inherent mechanics of dense epithelial monolayers at multicellular length scale might instruct individual cells to behave collectively. On the basis of these findings, we propose that mechanical resilience, obtained by a certain extent of cell jamming, allows the epithelium to perform efficient collective migration during wound healing

Hierarchical Approach for Comparing Collective Behavior Across Scales : Cellular Systems to Honey Bee Colonies

How individuals in a group lead to collective behavior is a fundamental question across biological systems, from cellular systems, to animal groups, to human organizations. Recent technological advancements have enabled an unprecedented increase in our ability to collect, quantify, and analyze how individual responses lead to group behavior. However, despite a wealth of data demonstrating that collective behavior exists across biological scales, it is difficult to make general statements that apply in different systems. In this perspective, we present a cohesive framework for comparing groups across different levels of biological organization, using an intermediate link of “collective mechanisms” that connects individual responses to group behavior. Using this approach we demonstrate that an effective way of comparing different groups is with an analysis hierarchy that asks complementary questions, including how individuals in a group implement various collective mechanisms, and how these various mechanisms are used to achieve group function. We apply this framework to compare two collective systems—cellular systems and honey bee colonies. Using a case study of a response to a disturbance, we compare and contrast collective mechanisms used in each system. We then discuss how inherent differences in group structure and physical constraints lead to different combinations of collective mechanisms to solve a particular problem. Together, we demonstrate how a hierarchical approach can be used to compare and contrast different systems, lead to new hypotheses in each system, and form a basis for common research questions in collective behavior.publishe

Dynamic-SERS Optophysiology: A Nanosensor for Monitoring Cell Secretion Events

We monitored metabolite secretion near living cells using a plasmonic nanosensor. The nanosensor created from borosilicate nanopipettes analogous to the patch clamp was decorated with Au nanoparticles and served as a surface-enhanced Raman scattering (SERS) substrate with addressable location. With this nanosensor, we acquired SERS locally near Madin-Darby canine kidney (MDCKII) epithelial cells, and we detected multiple metabolites, such as pyruvate, lactate, ATP, and urea simultaneously. These plasmonic nanosensors were capable of monitoring metabolites in the extracellular medium with enough sensitivity to detect an increase in metabolite concentration following the lyses of MDCKII cells with a nonionic surfactant. The plasmonic nanosensors also allowed a relative quantification of a chemical gradient for a metabolite near cells, as demonstrated with a decrease in relative lactate to pyruvate concentration further away from the MDCKII cells. This SERS optophysiology technique for the sensitive and nondestructive monitoring of extracellular metabolites near living cells is broadly applicable to different cellular and tissue models and should therefore provide a powerful tool for cellular studies