How cyclic tensile stress promotes phenotypic alterations of normal epithelial cells

Abstract

Cells sense and respond to the changes in various physicochemical factors of their tissue microenvironment. For example, the cells of the developing mammary gland are subject to tensile stress especially during pregnancy and lactation, and the morphology of the gland is sensitively regulated by maintaining the original level of stress. According to previous research, the increase in intracellular tension of the mammary gland can disrupt the architecture of the glands, inducing malignant transformation of the constituent cells. However, very little is known about how the intracellular tension initiates phenotypic alterations of normal cells. In the present study, cyclic tensile stimuli were directly applied to the monolayer of mammary gland epithelial cells (MCF10A) to investigate how tensile stress may induce phenotypic alterations. Based on immunofluorescence images of nuclei and yes-associated protein (YAP), the morphological features of the stimulated cells were identified and compared to the unstimulated control. Surprisingly, 10% cyclic stretching at 0.5Hz promoted cellular proliferation. Moreover, the cell density was significantly higher in the stimulated cells with much reduced nuclear size compared to unstimulated control. Cyclic tension also promoted cellular proliferation in MCF10A cells even at high cell densities. Of possible candidates linked to these phenotypic alterations, the nuclear translocation of YAP was clearly shown in the stimulated cells. The nuclear YAP interacted with TEAD to regulate cellular proliferation through Cyr61, one of their target genes. The tension induced nuclear YAP was also accompanied by the EMT-like behavior of much-enhanced cell migration speed and an increase in the number of scattering cells from epithelial sheets.