The Role of Twist1 in Chronic Pancreatitis–Associated Pancreatic Stellate Cells

In a healthy pancreas, pancreatic stellate cells (PaSCs) synthesize the basement membrane, which is mainly composed of collagen IV and laminin. In chronic pancreatitis (CP), PaSCs are responsible for the production of a rigid extracellular matrix (ECM), which is mainly composed of fibronectin and collagen I/III. Reactive oxygen species (ROS) evoke the formation of the rigid ECM by PaSCs. One of the sources of ROS is NADPH oxidase (Nox) enzymes. Nox1 up-regulates the expression of Twist1 and matrix metalloproteinase (MMP) 9 in PaSCs from mice with CP. Here 1) the functional relationship between Twist1 and MMP-9, and other PaSC-produced proteins, and 2) the extent to which Twist1 regulates the digestion of ECM proteins in CP were determined. Twist1 induced the expression of MMP-9 in mPaSCs. The action of Twist1 was not selective to MMP-9 because Twist1 induced the expression of collagen I, collagen IV, fibronectin, TGF-β, and αSMA. Using luciferase assay, Twist1 in hPaSCs increased the expression of MMP-9 at the transcriptional level in a NF-ĸB dependent manner. The digestion of collagen I/III by MMP-9 secreted by PaSCs from mice with CP was dependent on Twist1. Thus, Twist1 in PaSCs from mice with CP induces the production of a rigid ECM and the transcription of MMP-9 in a NF-ĸB dependent mechanism that selectively displays a proteolytic activity toward collagen I/III.