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Matrix obstructions cause multiscale disruption in collective epithelial migration by suppressing leader cell
Ye Lim Lee1, Jairaj Mathur2, Christopher Walter2
1Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130.
Molecular Biology of the Cell
|June 28, 2023
Summary
Epithelial cells slow down and lose direction when encountering dense obstructions, a phenomenon influenced by cell-cell adhesions and protrusions. This obstruction sensitivity may define a cell's "mechanotype" for collective migration.
Area of Science:
- Cell Biology
- Biophysics
- Materials Science
Background:
- Physical changes in the extracellular matrix affect epithelial cell migration during disease and development.
- The impact of matrix topology disruptions on collective cell migration speed and coordination is not fully understood.
Purpose of the Study:
- To investigate how microfabricated substrate obstructions influence collective epithelial cell migration.
- To identify the cellular mechanisms underlying sensitivity to topological obstructions.
Main Methods:
- Microfabrication of substrates with precisely controlled stump geometry, density, and orientation.
- Live imaging of epithelial cell migration on obstructed substrates.
- Development and application of a lattice-based computational model.
- Experimental validation using MDCK and MCF10A cell lines with varying cohesiveness.
Main Results:
- Dense obstructions significantly reduce collective cell migration speed and directionality.
- Obstructions induce cell softening, contrasting with increased stiffness observed in leader cells on flat substrates.
- A balance between cell-cell adhesions and cellular protrusions is crucial for obstruction-sensitive migration.
- MDCK and alpha-catenin-depleted MCF10A cells exhibit reduced obstruction sensitivity compared to wild-type MCF10A cells.
Conclusions:
- Epithelial cells possess an "obstruction-sensitivity" that allows them to navigate topological challenges.
- This sensitivity is governed by a combination of microscale cell softening, mesoscale disorder, and macroscale multicellular communication.
- Obstruction sensitivity could serve as a defining cellular "mechanotype" for collective migration while maintaining intercellular communication.
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