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

TL;DR

This study combines experimental observations and computational modeling to show how dynamic fibronectin assembly by neural crest cells facilitates effective collective migration and prevents jamming.

Contribution

It introduces a new individual-based model demonstrating how ECM remodeling and cell interactions drive stream formation and prevent jamming during neural crest cell migration.

Findings

ECM remodeling creates scaffolds for cell streams

Contact guidance and cell-cell repulsion prevent stream breakage

Leader cells create ECM fibers while followers respond to cues

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.