The isotropic or anisotropic organization 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 organization. Combined experimentation and adaptation of Vicsek modelling demonstrates that the reorientation of cells relative to each other following 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 localizes to cell–cell collision zones where it downregulates actomyosin activity. Cell collision guidance fails without this mechanism in place, leading to isotropic matrix generation. The cross-referencing of alignment and TFAP2C gene expression signatures against existing datasets enables the identification and validation of several classes of pharmacological agents that disrupt matrix anisotropy.
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Primary accession data files are deposited at the NCBI Gene Expression Omnibus under GSE121536. The data that support the findings of this study are available from the corresponding author on reasonable request.
The code for the computational model continues to be developed and is available via the following link: https://github.com/wershofe/FibroblastMatrixModel. The version pertaining to this manuscript is called cellCellModel.
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We are indebted to Bioinformatics and Biostatistics, Light Microscopy (in particular D. Barry), Advanced Sequencing Facilities, Cell Services and the Biological Research Facility at the Francis Crick Institute for scientific and technical support throughout the project. We thank C. Mein (Barts and the London School of Medicine and Dentistry) for support and advice with RNA sequencing. E.S., D.P., P.A.B. and E.W. were funded by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001144, FC001003), the UK Medical Research Council (FC001003, FC001144) and the Wellcome Trust (FC001003, FC001144). E.S. and D.P. also received funding from Breast Cancer Now (2013NovPR182). X.T. received funding from by the Spanish Ministry of Science and Innovation (Severo Ochoa Award), the Generalitat de Catalunya (Cerca Program), the European Research Council (CoG-616480), the European Commission (FET Proactive 731957) and Obra Social ‘La Caixa’. A.L. received financial support through the Junior Leader Postdoctoral Fellowship Programme from ‘La Caixa’ Banking Foundation.
The authors declare no competing interests.
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Supplementary Figs. 1–6 and Tables 1 and 2.
Alignment emerges prior to confluence and early migration paths predict final organization.
Actomyosin is supressed at cell contacts during collision guidance.
Actomyosin is concentrated at cell contacts during CIL.
Myosin is supressed at cell contacts during nematic gliding.
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Park, D., Wershof, E., Boeing, S. et al. Extracellular matrix anisotropy is determined by TFAP2C-dependent regulation of cell collisions. Nat. Mater. (2019) doi:10.1038/s41563-019-0504-3
Nature Reviews Physics (2019)