Regulation of Pancreatic Fibrotic Responses by Pigment Epithelium-Derived Factor (PEDF)

Replacement of normal tissue with fibrosis is central to the pathogenesis of both chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Fibrosis in CP results in loss of function while the fibrotic response in PDAC accelerates tumor growth and impairs treatment. Pancreatic fibrosis is  mediated by resident fibroblasts termed pancreatic stellate cells (PSC) which change from a quiescent state to an activated fibrotic phenotype.1, 2 Although the mediators of PSC activation have been extensively described,1 little is known about the regulators that keep PSC inactive.  Best characterized as a potent angiogenesis inhibitor in tumor biology studies, pigment epitheliumderived factor (PEDF) is an endogenous regulator of fibroblast quiescence. The addition of PEDF to fibroblasts inhibits their replication while its depletion allows for proliferation. In mice, absence of PEDF results in liver stellate cell activation. Moreover, in diseases associated with activated stellate cells, tissue PEDF levels are depleted by proteolytic degradation, thereby accentuating the loss of a signal that maintains fibroblast quiescence. Thus, PEDF maintains fibroblasts in their normal inactive state.  To test PEDF’s role in pancreatic fibrosis, two experimental approaches are proposed. The first involves induction of pancreatitis in PEDF-deficient and control mice. If PEDF functions to keep fibroblasts in a quiescent state, more injury and fibrosis should occur in PEDF-deficient animals. The second involves testing whether PEDF-containing microspheres can reverse the PSC activation observed in PEDF-/- mice and the fibrosis associated with PDAC. We hypothesize that chronic pancreatitis responses will be more severe in PEDF-deficient mice while PEDF treatments will diminish fibrosis in the PEDF-/- mice and that induced by a tumor model. These findings have clinical implications since PEDF treatments have already been used in human trials for patients with ocular diseases. Thus, positive findings in the proposed studies have potential clinical applications.