The capability of cells to retain the mechanosensitivity developed from different stiffness environments has been investigated by a cellular mechanobiology research groupfrom Washington University in St. Louis. The group, led by Amit Pathak, has established that cells acclimatize to a stiff surface and retain their “mechanical memory” when moved onto a soft surface, affecting their migratory behaviour (Biomaterials 146 146).
Cells are known to interact with their extracellular environment (the extracellular matrix, or ECM), with different tissues’ ECM having different physical and architectural properties. The physical stiffness of the ECM will affect cell migration and the translation of mechanical provocations to intracellular pathways. These cell behaviours, in relation to ECM stiffness, can be replicated and tested by placing cells on surfaces with different mechanical properties, enabling the testing of different microenvironments on epithelial cells.
Migration mechanics
The researchers discovered this mechanical memory through priming the cells on a stiff substrate, followed by subsequent migration to a soft substrate, where the cells retained previous migratory behaviour adopted during priming. This led to the conclusion that mechanical forces will affect cell genetics and behaviour. Overall, this affects the ability of a cell to attach to surrounding surfaces (i.e. the ECM) and migrate through tissues.
Some intracellular regulators of protein expression are also triggered by mechanical forces. When cells are placed on stiff surfaces these regulators are moved into position to increase protein expression for certain mechanisms. The translocation of a protein called yes-associated protein (YAP) to a cell’s nucleus will prime a cell for stiffness-sensitive migration. The research group showed that this mechanical memory is caused by YAP, as when YAP is deleted, this memory is lost. With YAP removed from the cellular arsenal of proteins, cells migrate across the soft surface in the same way as they do across the stiff surface.
Hydrogel-ECM stiffness
To mimic the ECM and alter the stiffness of the surface, the researchers used tuneable materials called hydrogels. Hydrogels are highly water-saturated polymeric structures, with the physical properties of a solid. In the model developed in this study, they fabricated a hydrogel construct with both a stiff and a soft section. Having regions of stiff and soft hydrogel combined within the same construct allows for seeding of cells on the stiff portion of hydrogel and easy monitoring of cell motility. This enabled the researchers to investigate cell behaviour after priming in the stiff region and movement to the softer hydrogel region.
Primed for the future
The findings from this study exemplify the importance of YAP and ECM stiffness in cell migration. These results illuminate the processes involved with cellular mechanical memory and its influence on cell migration. This can lead to insights into many different biological processes; with cellular invasion during cancer, wound healing and morphogenesis suggested as potential applications for these findings.
The authors state that potential limitations of this research arise from the use of non-physiologically relevant immortalized cell lines, which are able to proliferate freely. Also, the model presented utilizes a 2D platform for cells, unlike the in vivoenvironment where cells would be encapsulated within a 3D ECM. The information gained from these experiments, however, provides the basis for further experiments in more physiologically relevant models and cell types – potentially invaluable to research into cell migration.
