Abstract
The isotropic or anisotropic organisation of biological extracellular matrices has important consequences for tissue function. We study emergent anisotropy using fibroblasts that generate varying degrees of matrix alignment from uniform starting conditions. This reveals that the early migratory paths of fibroblasts are correlated with subsequent matrix organisation. Combined experimentation and adaptation of Vicsek modelling demonstrates that the reorientation of cells relative to each other upon collision, plays a role in generating matrix anisotropy. We term this behaviour cell collision guidance. The transcription factor TFAP2C regulates cell collision guidance, in part by controlling the expression of RND3. RND3 localises to cell-cell collision zones where it locally down-regulates actomyosin activity. Without this mechanism in place cell collision guidance fails leading to isotropic matrix generation. Cross-referencing alignment and TFAP2C gene expression signatures against existing datasets enables the identification and validation of several classes of pharmacological agents that disrupt matrix anisotropy.
Highlights
The extracellular matrix (ECM) is a scaffold of fibrillar proteins and proteoglycans that maintains the structure of tissues
Greater matrix alignment was seen in murine mammary tumours compared to normal tissue, the extent of alignment varied between regions
Having established a role for TFAP2C in cultured fibroblasts, we investigated if its expression correlated with cell and ECM organisation in normal and cancerous human tissues
Summary
The extracellular matrix (ECM) is a scaffold of fibrillar proteins and proteoglycans that maintains the structure of tissues. Abercrombie described the ability of fibroblasts to interact with and influence neighbouring cells via Contact Inhibition of Locomotion (CIL), which involves repolarisation and changing direction upon contact[11,12]. This behaviour depends on actomyosin contractility at the point of cell-cell contact and plays a role in tissue patterning[13,14,15,16,17,18]. Several models have considered self-propelled particles and inelastic collisions between particles In these models, collision properties influence alignment, but these models lack the complex biological signalling that determines cell collision behaviour 22,23,24,25. Attribute the higher order alignment to communication between fibroblasts via the ECM, while Duclos et al, observe that following mitosis daughter cells have similar orientation, as cells proliferate they form locally ordered regions
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
