Speaker
Description
"Introduction
Tissue growth in defects is controlled by the local curvature of the substrate and is traditionally regarded to follow the same process of cell organization from large to small defects [1]. At defect dimensions of 100s of µms to a few mms, tissue growth typically follows a centripetal process driven by an inner ring composed of contractile and proliferative cells. In contrast, the closure of very small defects with a diameter of 10s of µms, cell protrusions seem to contribute to defect closure. Here, we investigated how curvature drives cells from the previously described layer-by-layer tissue growth into defect closure and we reveal a curvature-driven “cell suturing” process that is most pronounced in stromal cells.
Methodology
The response of different cell types (i.e., fibroblasts, mesenchymal stromal cells, osteoblasts, pre-osteoblasts and endothelial cells) to surface curvature was characterized using micro-engineered cell culture substrates featuring half-cylindrical environments with controlled curvature variation. Collective cellular self-organization and gap closure was analyzed inside well-defined 3D cylindrical pores as well as in a biomaterial environment featuring channel-like pores with more stochastic geometrical conditions. Lastly, micro-wounds were introduced in an in vitro tissue growth setup to observe the transition between different modes of cell organization during wound healing.
Results
Cellular response to curvature is dependent on the cell type and degree of curvature. While on large curvatures (i.e., diameter > 300 µm) stromal cells prefer to align following the direction of higher curvature, as the curvature increased (i.e., diameter < 300 µm), cells adapt to curvature via two well-differentiated mechanisms: alignment towards the minimum curvature or lifting from the substrate along the maximum curvature. The occurrence of cell lifting was correlated with the distribution of the focal adhesions around the cell and can be regulated by the cytoskeletal stress state or the stiffness of the substrate. Cells without lifting capability lead to a process of centripetal gap closure. However, cellular processes involving cell lifting induced a significantly faster suture-like wound healing mechanism compared to the previously described centripetal gap closure.
Conclusion
Fundamental differences were found in how distinct cell types respond to curvature within gaps of few 100s of micrometers. In living tissues, such gaps could represent meso-scale defects occurring i.a., after tissue delamination consequence of mechanical overloading or injury, but such micro-defects may also be engineered in synthetic porous materials. Based on our findings, cells may be classified into types capable to close micro-defects through an extremely efficient suture-like process and cell types that favor a layer-by-layer gap filling associated with a circular lumen shape and slower defect closure. Addressing the fast gap closure resulting from the cell suturing-mode in biomaterial strategies is regarded advantageous for material-driven tissue healing and regeneration. This can be achieved by implementing appropriate curvatures into porous materials that provoke cell suturing for the individual cell type of interest [2].
References
- Bidan, C.M., et al., Adv. Healthc. Mater. 2, 186-194 (2013).
- Petersen, A., et al., Nat. Commun. 9, 4430 (2018)."
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