Compressive Stress Causes an Unjamming Transition and an Epithelial–Mesenchymal Transition in the Airway Epithelium in Asthma

One of the major characteristics of asthma is bronchospasm, which is caused by excessively contracted smooth muscle and results in buckling of the airway epithelium. Buckling of the epithelium imposes compressive mechanical stress on the airway epithelial cells. We previously reported that compressive mechanical stress, which is similar to stress that occurs during bronchospasm, induces airway remodeling in well-differentiated primary human bronchial epithelial (HBE) cells maintained in air–liquid interface culture. In this study, we investigated the physical behavior of HBE cells cultured from normal donors and donors with asthma to gain a better understanding of the mechanobiology of airway epithelial cells.

We captured time-lapse images of HBE cells and quantified cellular motions. In normal cells, the transition from an unjammed state, in which cells flow like a fluid and rearrange with neighbors frequently, to a jammed state, in which cells move little, like a solid, and rearrange infrequently, occurred between Days 6 and 8 in air–liquid interface culture, but in asthmatic cells the transition was delayed until Day 14 (1). Also, in cell lysates from Days 6 through 14, the existence of vimentin was temporally correlated with the onset of the jamming transition. Treatment of asthmatic cells with SB431542, a transforming growth factor-β receptor inhibitor, accelerated the jamming transition and the disappearance of vimentin. Furthermore, compressive stress caused the jammed cells to transition to an unjammed state, but pretreatment with SB431542 attenuated the compressive stress-induced unjamming transition. Repeated applications of compressive stress induced the expression of vimentin and slug (epithelial–mesenchymal transition marker proteins) but reduced claudin-1 (a tight junction protein).

Maturation of unjammed HBE cells causes a jamming transition, whereas compression of the jammed HBE cells causes an unjamming transition. Importantly, transforming growth factor-β controls the jamming transition and associated vimentin expression, and compressive stress induces EMT. These findings suggest that the jamming–unjamming transition is a novel physical feature that captures injury-repair processes and differentiates the normal epithelium from the asthmatic epithelium.