Combined Experimental and Mathematical Approach for Development of a Microfabrication-Based Model to Investigate Cell-Cell Interaction During Migration

Cell migration is determined by an inherent motility as well as signaling cues received from interaction with neighboring cells. Singular and collective migration of cells is a key determinant of various pathological conditions, such as metastasis, wound healing response and immune surveillance. Current in vitro migration models possess a number of drawbacks that limit quantitative investigation of cell-cell interactions in migration in a heterogeneous microenvironment. The objective of this study is to develop a two-dimensional migration model by combining experimental and mathematical tools to quantify the role of homotypic and heterotypic interaction during migration.An experimental model containing cellular micropatterns (cell islands) was developed by microfabrication techniques including photo- and soft-lithography. Breast cancer cells were used to determine the effect of island geometry (initial area and shape), ECM and growth factor in regulating migration. Subsequently, breast cancer and stromal cells were spatially patterned and co-cultured to establish cell-cell interaction between homotypic (cancer) and heterotypic (stromal) cells. The findings from this model show that local geometry as well as heterotypic interactions can regulate cell island migration significantly. The model was extended to evaluate epithelial migration quantitatively by using human keratinocytes. It was further used to obtain insights into the contribution of non-muscle myosin signaling cascade during migration. Pharmacological inhibition of selected components showed that non-muscle myosin II was differentially involved in regulating cell shape and migration in keratinocytes, via distinct pathways controlled by upstream kinases. A mathematical model of island motility in an interacting cell population was developed based on the generalized mass transport approach described by Stefan-Maxwell’s equation. In this model, cancer-stromal interaction was simulated in the presence of varying cell density ratios. It was shown that at equal or higher stromal densities this model predicted a biphasic cancer migration profile with respect to initial island area, thus implying that greater cell-cell interactions can alter migration characteristics of cell islands.In conclusion, the combined experimental and mathematical model can be used as a quantitative approach to study the impact of cell-cell interactions on migration. It can be readily applied to multi-cellular environments in vitro, e.g., skin and cartilage tissue engineering, with potential extension to in vivo situation, e.g., tumor metastasis.