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During wound healing, tumor growth, and organ formation, epithelial cells migrate and cluster in layered tissue environments. Although cellular mechanosensing of adhered extracellular matrices is now well recognized, it is unclear how deeply cells sense through distant matrix layers. Since single cells can mechanosense stiff basal surfaces through soft hydrogels of <10 μm thickness, here we ask whether cellular collectives can perform such “depth-mechanosensing” through thicker matrix layers. Using a collagen-polyacrylamide double-layer hydrogel, we found that epithelial cell collectives can mechanosense basal substrates at a depth of >100 μm, assessed by cell clustering and collagen deformation. On collagen layers with stiffer basal substrates, cells initially migrate slower while performing higher collagen deformation and stiffening, resulting in reduced dispersal of epithelial clusters. These processes occur in two broad phases: cellular clustering and dynamic collagen deformation, followed by cell migration and dispersal. Using a cell-populated collagen-polyacrylamide computational model, we show that stiffer basal substrates enable higher collagen deformation, which in turn extends the clustering phase of epithelial cells and reduces their dispersal. Disruption of collective collagen deformation, by either α-catenin depletion or myosin-II inhibition, disables the depth-mechanosensitive differences in epithelial responses between soft and stiff basal substrates. These findings suggest that depth-mechanosensing is an emergent property that arises from collective collagen deformation caused by epithelial cell clusters. This work broadens the conventional understanding of epithelial mechanosensing from immediate surfaces to underlying basal matrices, providing insights relevant to tissue contexts with layers of varying stiffness, such as wound healing and tumor invasion.
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Cell-to-cell influence on growth in large populations
Recent studies have revealed the importance of outlier cells in complex cellular systems. Quantifying heterogeneity in such systems may lead to a better understanding of organ engineering, microtumor growth, and disease models, as well as more precise drug design. We used the ability of quantitative phase imaging to perform long-term imaging of cell growth to estimate the “influence” of cellular clusters on their neighbors. We validated our approach by analyzing epithelial and fibroblast cultures imaged over the course of several days. Interestingly, we found that there is a significant number of cells characterized by a medium correlation between their growth rate and distance (modulus of the Pearson coefficient between 0.25-.5). Furthermore, we found a small percentage of cells exhibiting strong such correlations, which we label as “influencer” cellular clusters. Our approach might find important applications in studying dynamic phenomena, such as organogenesis and metastasis.
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- Award ID(s):
- 1735252
- PAR ID:
- 10110998
- Date Published:
- Journal Name:
- Biomedical optics express
- Volume:
- 10
- Issue:
- 9
- ISSN:
- 2156-7085
- Page Range / eLocation ID:
- 4664-4675
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
-
Accepted Manuscript
- Journal Article:
- https://doi.org/https://doi.org/10.1364/BOE.10.004664
