Integer topological defects organize stresses driving tissue morphogenesis
Preprint posted on 2 June 2020 https://www.biorxiv.org/content/10.1101/2020.06.02.129262v1
Article now published in Nature Materials at http://dx.doi.org/10.1038/s41563-022-01194-5
A peek into the dynamic patterns of myoblasts around integer defects.
Selected by Yamini Ravichandran, Giulia PaciCategories: biophysics, cell biology, developmental biology
Background
Long-range alignment and collective motion can be observed in biological systems across scales, from cytoskeletal filaments to bacteria, cells and even entire organisms like fish schools. These systems can be described as nematic liquid crystals [1], formed by elongated elements with a long-range orientational order. Importantly, biological systems are active, meaning that the elements can self-propel through energy-consuming processes, creating stresses. When neighbours have mismatched orientations, topological defects can arise, causing a local disruption of the orientation field. These defects can be classified based on their topological strength s, which indicates the change in the orientation of molecules around the singular points around a 360° rotation.
Half-integer defects (s = ± 1/2) have been observed in several biological systems including cell colonies and monolayers, where they have correlations with changes in cell density and extrusion events [2, 3]. The role of integer defects (s = ±1) in living systems is, on the other hand, still unknown: here, Guillamat et al. investigate their role in modelling tissues.
Approach and observations
A circular confinement below the inter-defect characteristic length is applied to myoblast C2C12 cells by seeding them on disc micropatterns, after which they are let to proliferate and create a monolayer. The cell density within the monolayer determines the fate of the self-organization patterns that occur around integer topological defects.
Two patterns of organization corresponding to s = ±1 defects are observed in the monolayers: spirals and asters (Figure). Upon reaching confluence, the cells self-organize into spiral patterns with persistent rotation that can be stabilized by chemically inhibiting further proliferation. Asters are observed when the cells exhibiting a spiral pattern continue to proliferate, and cease rotating.
After transitioning from spirals to asters further proliferation leads to the formation of cellular mounds in the center. The 3D organization of the mounds reveals that they present aster-to-spiral transitions from the bottom to the top of the mound, capable of generating differentiated myotube-like structures. Contrarily, upon adding C2C12 cells incapable of differentiation cellular mounds turn into cylindrical multicellular protrusions.
To dissect the stress fields present in the monolayer, the authors employed particle image velocimetry (PIV) to measure the velocity and orientation fields and developed a 2D active nematic theory, which is described in two associated preprints [4,5]. Stress patterns in the center of the aster are probed by a micropillar constriction assay, which consists in seeding cells in a circular confinement with micropillars placed strategically in the center. Deformations induced on the base of the pillar by the cells are quantified to measure the forces exerted by the cells in asters.

Key findings
-
Increased cell density triggers spirals-to-asters transitions in monolayers and the reverse is true for asters-to-spirals transitions in cellular mounds
-
Formation of these self-organized cellular structures is strictly dependent on the circular confinement, in the absence of which mounds and protrusions collapse.
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The stress patterns generated by aster defects can trigger localized differentiation, in this case with the presence of multinucleated myotube-like structures.
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Integer topological defects can organize multi-cellular stresses required for tissue morphogenesis
Why this work is important?
This work investigates for the first time the active mechanics of integer topological defects, showing that they can localize myoblast differentiation and the formation of 3D protrusions.
Questions for the authors
-
What about extrusion events in these cellular mounds? Couldn’t cell extrusion compensate for the stress experienced in the core of cellular mounds?
-
With regard to active anisotropic cytoskeletal stress gradients would you be interested in studying Cdc42/Rac gradients and how they could influence collective cellular rearrangements in these patterns?
- How important is the size of fibronectin-coated discs to obtain self-organized patterns around integer defects? Did you ever observe more than an individual integer defect (e.g. using larger discs)?
References
[1] Doostmohammadi, A., Ignés-Mullol, J., Yeomans, J. M., & Sagués, F. (2018). Active nematics. Nature communications, 9(1), 1-13.
[2] Kawaguchi, K., Kageyama, R., & Sano, M. (2017). Topological defects control collective dynamics in neural progenitor cell cultures. Nature, 545 (7654), 327-331.
[3] Saw, T. B., Doostmohammadi, A., Nier, V., Kocgozlu, L., Thampi, S., Toyama, Y., … & Ladoux, B. (2017). Topological defects in epithelia govern cell death and extrusion. Nature, 544(7649), 212-216.
[4] Blanch-Mercader, C., Guillamat, P., Roux, A., & Kruse, K. (2020). Integer topological defects of cell monolayers–mechanics and flows. arXiv preprint arXiv:2006.01725.
[5] Blanch-Mercader, C., Guillamat, P., Roux, A., & Kruse, K. (2020). Quantifying material properties of cell monolayers by analyzing integer topological defects. arXiv preprint arXiv:2006.01575.
Posted on: 27 August 2020
doi: https://doi.org/10.1242/prelights.22399
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