Directional cell migration in an extracellular pH gradient: A model study with an engineered cell line and primary microvascular endothelial cells

Abstract

Extracellular pH (pHe) gradients are characteristic of tumor and wound environments. Cell migration in these environments is critical to tumor progression and wound healing. While it has been shown previously that cell migration can be modulated in conditions of spatially invariant acidic pHe due to acid-induced activation of cell surface integrin receptors, the effects of pHe gradients on cell migration remain unknown. Here, we investigate cell migration in an extracellular pHe gradient, using both model αvβ3 CHO-B2 cells and primary microvascular endothelial cells. For both cell types, we find that the mean cell position shifts toward the acidic end of the gradient over time, and that cells preferentially polarize toward the acidic end of the gradient during migration. We further demonstrate that cell membrane protrusion stability and actin–integrin adhesion complex formation are increased in acidic pHe, which could contribute to the preferential polarization toward acidic pHe that we observed for cells in pHe gradients. These results provide the first demonstration of preferential cell migration toward acid in a pHe gradient, with intriguing implications for directed cell migration in the tumor and wound healing environments.