“Mechanobiology of epithelial cells in physically heterogeneous environments”

Seminar | November 1 | 12-1 p.m. | 290 Hearst Memorial Mining Building

 Amit Pathak, Washington University in St. Louis

 Bioengineering (BioE)

The ability of epithelial cells to move through complex tissue barriers fundamentally regulates important physiological and pathological phenomena, such as embryogenesis, organ development, wound repair, and tumor metastasis. In pathogenesis, including fibrosis and cancer, matrix stiffening is known to induce epithelial-mesenchymal transition (EMT) and enhance cell migration in clustered epithelial cells. These processes result from a complex interplay of epithelial cells with physically heterogeneous extracellular matrices (ECMs) of varying stiffness and topography, spanning over multiple scales of time and space. In this presentation, I will discuss two broad topics within my research group – (1) induction of EMT due to matrix confinement and physical defects, and (2) role of mechanical memory in cell migration. Topic 1: We fabricate hydrogel-based microchannels to show that epithelial cells express EMT markers in more confined channels, even in soft ECMs that otherwise protect against such mechano-activation. Through experimental measurements and computer simulations, we show that cell spreading and elongation along channel walls is essential for this confinement-sensitive EMT. In a related project, we show that physical defects in a basement membrane-like soft matrix induce EMT, which is distinct from the known mechanosensitive EMT due to matrix stiffness or topography. Topic 2: We interrogate whether priming of epithelial cells by a given matrix stiffness influences their future migration on a different matrix. Through experimental results and computational modeling, I will discuss how YAP-dependent mechanical memory and dynamic mechanotransduction enable the collectively migrating cells to sense matrix stiffness of both past and present.