(502g) Invited Talk: Mechanobiology of TGF?-Mediated Signaling and Cell Fate

Transforming growth factor (TGF)-β1 is a multifunctional cytokine that plays important roles in health and disease. Previous studies have revealed that TGFβ1 activation, signaling, and downstream cell responses, including epithelial-mesenchymal transition (EMT) and apoptosis, are regulated by chemical and mechanical cues. However, how microenvironmental physical properties mechanistically impact cell fate decisions downstream of TGFβ1 has not been fully elucidated. Through the use of engineered materials with controlled mechanical properties, we show that matrix stiffness regulates the subcellular localization and activity of histone methyltransferases in response to TGFβ1, thereby impacting histone modifications, gene expression, and EMT. Furthermore, we demonstrate that matrix viscous dissipation regulates TGFβ1-induced changes in cell morphology, cytoskeletal organization, and gene expression. These effects are mediated by mechanoresponsive signaling molecules, including integrin linked kinase (ILK) and yes-associated protein (YAP). Together, these studies provide insight into how microenvironmental mechanical properties regulate cell fate decisions in response to growth factors and may suggest approaches for targeting TGFβ1-mediated signaling to enhance wound healing and suppress fibrosis and cancer.