A Geometric-Tension-Dynamics Model of Epithelial Convergent Extension by Claussen et al.

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Tissue flow in epithelial convergent extension is driven by positive feedback on myosin-generated cytoskeletal tension, and the extent of this flow is limited by the initial cell packing order, as demonstrated through a geometric-tension-dynamics model.

Samenvatting

• Bibliographic Information: Claussen, N. H., Brauns, F., & Shraiman, B. I. (2024). A Geometric Tension Dynamics Model of Epithelial Convergent Extension. arXiv preprint arXiv:2311.16384v3.
• Research Objective: To develop a model of epithelial tissue mechanics in the tension-dominated regime that explains how positive feedback on myosin-generated tension drives convergent extension and how initial cell packing order affects the extent of tissue flow.
• Methodology: The researchers developed a computational model based on vertex models, where epithelial tissue is represented as a polygonal tiling. The model incorporates two key assumptions: (1) forces in the epithelium are approximately balanced on morphogenetic timescales, and (2) active cortical tensions dominate over other sources of stress. The model simulates tissue mechanics using a two-step minimization of elastic energy: first, achieving force balance of cortical tensions, and second, minimizing cell shape energy. Positive feedback on cortical tensions is implemented, leading to cell rearrangements (T1 transitions) and tissue deformation. The model is used to simulate convergent extension in irregular cell arrays with varying initial packing order and tension anisotropy. A local tension configuration (LTC) order parameter is introduced to quantify the shape of tension triangles and analyze the dynamics of local tension configurations.
• Key Findings:
  • The model successfully reproduces key features of convergent extension observed in the Drosophila germ band, including the slowdown of tissue flow after approximately twofold elongation and the concomitant loss of order in cell packing.
  • Simulations reveal that initial cell packing order significantly influences the extent of convergent extension. Higher initial order leads to more efficient and extensive tissue flow.
  • Analysis of local tension configurations shows that positive feedback on tension leads to the formation of tension "bridges" (obtuse tension triangles), which are more efficient at driving cell rearrangements than tension "cables" (acute tension triangles).
  • The model predicts that saturating tension feedback, in contrast to the "winner-takes-all" feedback used in the primary model, leads to the formation of tension cables and reduced convergent extension.
  • Simulations incorporating both active and passive tissue regions, mimicking the Drosophila embryo, reproduce the characteristic tissue flow pattern observed during germ band elongation.
• Main Conclusions:
  • The study provides a mechanistic understanding of how positive feedback on myosin-generated tension drives convergent extension in epithelial tissues.
  • The model highlights the crucial role of initial cell packing order in determining the extent of tissue flow, explaining the self-limiting nature of convergent extension observed in biological systems.
  • The research suggests that local cell geometry, particularly the configuration of tension triangles, contains important morphogenetic information.
• Significance: This study advances our understanding of the mechanical principles underlying epithelial morphogenesis and provides a framework for investigating the role of cell-scale mechanics in tissue-level shape changes during development.
• Limitations and Future Research: The current model is two-dimensional and does not account for out-of-plane deformations or cell divisions. Future research could extend the model to three dimensions and incorporate cell proliferation to capture a wider range of morphogenetic processes. Further investigation into the specific molecular mechanisms underlying positive tension feedback and the regulation of cell shape elasticity is also warranted.

Statistieken

Tissue flow stalls after approximately 2-fold convergent extension.
The peak of tension anisotropy in the ordered initial condition coincides with the onset of T1 transitions and the decay of the fraction of cells with six neighbors (p6).
Simulations with saturating tension feedback produce very little convergent extension, with approximately 20% of T1 transitions being reversible.

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A Geometric Tension Dynamics Model of Epithelial Convergent Extension

by Nikolas H. C... om arxiv.org 10-04-2024

https://arxiv.org/pdf/2311.16384.pdf

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How might the incorporation of cell signaling pathways, which can influence myosin activity and cell adhesion, affect the dynamics of convergent extension in this model?

Incorporating cell signaling pathways would significantly enrich the model's realism and predictive power, as these pathways play a crucial role in modulating convergent extension. Here's how:

Spatial Patterning of Tension Dynamics: Signaling pathways, such as the Wnt/PCP pathway, are known to establish planar cell polarity, which in turn directs the localization and activity of myosin motors. The model could incorporate this by spatially modulating the parameters of the tension feedback mechanism (Eq. 5). For instance, cells receiving specific signals could exhibit stronger positive feedback, leading to higher tension anisotropy and promoting localized T1 transitions. This would enable the model to capture more complex morphogenetic events beyond simple, uniform convergent extension.

Regulation of Cell Adhesion: Cell signaling can also regulate the strength of cell-cell adhesion, influencing the ease with which cells rearrange. The model could incorporate this by dynamically adjusting the timescale of passive tension relaxation (τp) in response to signaling cues. For example, signals promoting cell-cell adhesion could increase τp, making rearrangements less frequent, while signals downregulating adhesion could decrease τp, facilitating T1 transitions.

Integration of Multiple Morphogenetic Events: Signaling pathways often act as integrators of various morphogenetic processes. By incorporating these pathways, the model could link convergent extension to other events like cell division, apoptosis, or changes in cell shape. This would allow for a more holistic understanding of how different cellular processes are coordinated during tissue development.

Response to External Cues: Signaling pathways often mediate the response of tissues to external cues, such as morphogen gradients. Incorporating these pathways would enable the model to predict how convergent extension is modulated by external factors, providing a more comprehensive framework for understanding tissue morphogenesis in complex environments.

Could external mechanical cues or constraints, such as those imposed by surrounding tissues, override the limitations imposed by initial cell packing order and allow for more extensive convergent extension?

Yes, external mechanical cues or constraints can significantly influence convergent extension and potentially overcome the limitations imposed by initial cell packing order. Here's how:

Overriding Local Disorder: While the model demonstrates that initial cell packing order is crucial for efficient convergent extension, external forces can impose a global directional bias on the tissue, overriding the effects of local disorder. This external guidance can help align tension anisotropy and promote coordinated T1 transitions even in tissues with initially suboptimal packing.

Sustaining Tension Anisotropy: The model shows that convergent extension becomes self-limiting as cell rearrangements disrupt the initial order. External forces, such as those exerted by surrounding tissues, can act as a "template" to maintain or even enhance tension anisotropy. This sustained anisotropy can drive further cell intercalations, leading to more extensive convergent extension than possible in isolation.

Modifying the Energy Landscape: External constraints can alter the energetic landscape of the tissue, influencing the preferred directions of cell rearrangements. For example, confinement within a specific geometry can bias T1 transitions to occur predominantly along a specific axis, promoting elongation in that direction.

Inducing Secondary Ordering: External mechanical cues can induce secondary ordering in the tissue, even if the initial packing is disordered. For instance, sustained shear stress can lead to the alignment of cell shapes and the emergence of a more ordered configuration over time, facilitating more efficient convergent extension.

How can the insights gained from this model be applied to understand and potentially manipulate tissue morphogenesis in regenerative medicine or disease modeling?

The insights from this model have significant implications for regenerative medicine and disease modeling:

Guiding Tissue Engineering: The model highlights the importance of initial cell packing order and tension anisotropy for efficient convergent extension. This knowledge can be applied to engineer tissues with specific shapes and organizations. For instance, by controlling cell seeding density and applying external forces to manipulate tension, we could guide the growth of tissues with desired elongation patterns.

Developing Targeted Therapies: Understanding how local tension dynamics and cell rearrangements drive morphogenesis can aid in developing targeted therapies for diseases involving tissue malformation. For example, by identifying the specific signaling pathways or mechanical cues that are disrupted in a particular disease, we could potentially design interventions to restore normal tissue architecture.

Predicting Disease Progression: The model can be used to create more accurate in silico models of tissue development and disease progression. By incorporating patient-specific parameters, such as cell mechanics and signaling pathway activities, we could potentially predict the evolution of diseases like birth defects or cancer, enabling earlier diagnosis and personalized treatment strategies.

Enhancing Regenerative Capacity: The model's insights into the interplay between active tension and cell rearrangements can inform strategies to enhance the regenerative capacity of tissues. By manipulating the mechanical environment or modulating signaling pathways, we could potentially stimulate cell intercalation and promote the regeneration of damaged tissues.
Overall, this model provides a valuable framework for understanding the fundamental mechanisms of tissue morphogenesis. By incorporating additional biological complexities and integrating experimental data, it holds great promise for advancing regenerative medicine and disease modeling.