Zhenjun Deng1, Manon Subilia2, Dr. Yu Suk Choi1, Nicole Hortin1, Dr. Andrew Stevenson1, FRACS Fiona Wood1,3, A/Prof. Cecilia Prêle1, Dr. Mark Fear1
1The University Of Western Australia, Perth, Australia, 2Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland, 3Fiona Stanley Hospital, Perth, Australia
Keloid is driven in part by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence of fibroblast matrix deposition. Yes-associated protein (YAP) is a key mechanoactivated coordinator of fibroblast phenotype and matrix production and is translocated to the nucleus upon activation. Here, we have studied the impact of matrix stiffness on fibroblast phenotype by culturing fibroblasts on a stiff coverslip (>109 Pa), 2 kPa polyacrylamide (PA) hydrogel (normal dermis-equivalent stiffness), 20 kPa PA hydrogel (keloid-equivalent stiffness), and 40 kPa PA hydrogel (extreme pathological-equivalent stiffness). In this study, we found that matrices of pathological stiffness induced YAP nuclear translocation as did stimulation with TGF-β in normal fibroblasts. However, in contrast, keloid fibroblasts showed high and stable YAP activation which does not respond to increasing matrix stiffness, suggesting that keloid fibroblasts have lost the normal mechanism of mechanosensation. In addition there is no increase in nuclear YAP in response to increasing stiffness nor to treatment with TGF-β, suggesting keloid fibroblasts are autoregulated to produce higher levels of activated YAP irrespective of biological and physical cues.
Taken together, this data shows that normal skin fibroblasts respond to the physical properties of the matrix in vitro. However, keloid fibroblasts appear to have elevated activation of mechanotransduction pathways irrespective of the micro-environment. This change may significantly contribute to the pathogenesis of keloid and has implications for potential treatments to ameliorate keloid disease.
My name is Zhenjun Deng. I am a second year PhD student from the University of Western Australia. My PhD is focused on cells and extracellular matrix interaction and how these may be important in keloid pathology.