Dynamic fibronectin assembly and remodeling by leader neural crest cells prevents jamming in collective cell migration

Abstract

Collective cell migration plays an essential role in vertebrate development, yet the extent to which dynamically changing microenvironments influence this phenomenon remains unclear. Observations of the distribution of the extracellular matrix (ECM) component fibronectin during the migration of loosely connected neural crest cells (NCCs) lead us to hypothesize that NCC remodeling of an initially punctate ECM creates a scaffold for trailing cells, enabling them to form robust and coherent stream patterns. We evaluate this idea in a theoretical setting by developing an individual-based computational model that incorporates reciprocal interactions between NCCs and their ECM. ECM remodeling, haptotaxis, contact guidance, and cell-cell repulsion are sufficient for cells to establish streams in silico, however additional mechanisms, such as chemotaxis, are required to consistently guide cells along the correct target corridor. Further model investigations imply that contact guidance and differential cell-cell repulsion between leader and follower cells are key contributors to robust collective cell migration by preventing stream breakage. Global sensitivity analysis and simulated gain- and loss-of-function experiments suggest that long-distance migration without jamming is most likely to occur when leading cells specialize in creating ECM fibers, and trailing cells specialize in responding to environmental cues by upregulating mechanisms such as contact guidance.

Lens Placode Modulates Extracellular Matrix Formation During Early Eye Development

“…In addition to the gelatinase activity, NCC migration remodels fibronectin to a fibrillar-pattern. This process is called fibrillogenesis, and is critical for the neural crest cells migration (Martinson et al, 2023). In this context, the punctual pattern of fibronectin between the placode and the optic vesicle could also contribute to inhibit NCC entry to this region during early lens development.…”

A simple framework for agent-based modeling with extracellular matrix

“…To address non-local remodeling of ECM, future efforts will focus on incorporating the option for a continuous, force-based ECM model, for example as a visco-poroelastic material using a finite element approach, then sampling the variables established in this work on the ECM element grid. To address the current limit of remodeling only a single ECM element, we aim to explore approaches to spread remodeling over multiple, adjacent ECM elements, for example with Gaussian smoothing or other techniques as well as enabling ECM influence on cell behavior from multiple ECM elements [55, 60]. Similarly, we aim to enable extending bidirectional cell-ECM interactions such that cells that span multiple elements can alter variables in each element it spans and be behaviorally influenced by them.…”

“…Another possible extension is varying fiber following stochastically by sampling from a range of travel angles instead of deterministic contact guidance. Stochastic contact guidance was recently implemented using sampling from a von Mises distribution [60], showing its feasibility and interest within the community. Moreover, in future releases, we plan to generalize the framework architecture to enable users to easily replace built in constitutive relationships with their own relationships.…”

“…In particular, leader cells follow oxygen gradients with a high chemotactic bias and encode their movements via ECM remodeling (see Section 7.1 for mathematical details). Followers’ movements are influenced by signals in the ECM (contact guidance) and are chemotactic with bias equal to local value of a (Chemotaxis Model II - Equation 16) following previous works that used chemotactic bias [59, 60]. They read signals in the ECM with a high sensitivity ( s = 1.0) and are incapable of remodeling ECM.…”

“…In a later paper, the model is further extended to combine chemotactic and ECM contact guidance, still in the context of wound healing [59]. Finally, in work similar to Dallon, Sherratt, and colleagues, Martinson et al use a deposition of discrete ECM puncta followed by cellular realignment of the fibers to study collective migration of neural crest cells using both number of ECM puncta and their orientations to alter cell motion [60].…”