Fig. 4

Regulation of myofibroblast formation by TGF-β1. a Schematic presentation of TGF-β1 signaling in myofibroblast formation. Upon stimulation, latent TGF-β1 is activated and active TGF-β1 is released to bind to its receptors on the cell surface to drive the Smad-dependent pathway, which directly up-regulates the transcription of fibrotic genes encoding α-SMA, collagens, and fibronectin. Binding of active TGF-β1 to its receptors also elicits a number of Smad-independent pathways, such as the PI3K-AKT signaling, which may promote myofibroblast differentiation and function. b Role of TGF-β1 in CNT-stimulated myofibroblast differentiation. CNTs induce the production and secretion of TGF-β1 by macrophages and epithelial cells, which serves as a paracrine factor to stimulate fibroblast-to-myofibroblast differentiation. CNTs also directly induce fibroblasts to produce and secrete TGF-β1, which functions as an autocrine factor for fibroblasts to differentiate into myofibroblasts. CNTs may directly promote fibroblast-to-myofibroblast differentiation by mimicking the ECM or intracellular collagen fibers to generate mechanical stress. In addition, CNTs stimulate epithelial cells to produce and secrete TGF-β1, which may induce the trans-differentiation of epithelial cells to myofibroblasts via EMT