Indian hedgehog promotes the migration of rat activated pancreatic stellate cells by increasing membrane type-1 matrix metalloproteinase on the plasma membrane

Indian hedgehog (Ihh) is a member of hedgehog peptides family that exerts diverse effects on multiple cellular functions. Since Ihh expression is elevated in the pancreas of chronic pancreatitis patients, Ihh has been assumed to participate in the chronic pancreatic injury, especially in pancreatic fibrosis. However, its function in pancreatic fibrosis is still unknown. We thus examined Ihh effects on rat activated pancreatic stellate cells (PSCs) that play a central role in pancreatic fibrosis. Activated PSCs express both patched-I and smoothened that are essential components of hedgehog receptor system. Ihh did not alter the PSC expression of collagen-I or alpha-smooth muscle actin, a parameter of PSC transformation, or did not change PSC proliferation. However, Ihh enhanced PSC migration in both chemotactic and chemokinetic manners. Furthermore, Inn increased the amount of membrane-type I matrix metalloproteinase (MTI-MMP) and altered its localization on the plasma membrane, which plays a stimulatory role in cellular migration. In addition, tissue inhibitor of metalloproteinase-2 (TIMP-2) attenuated lhh-stimulated PSC migration. Since most hedgehog intracellular signals are mediated by Gli-I transcription factor, we investigated its contribution to lhh-enhancement of PSC migration. Ihh induced Gli-I nuclear accumulation in PSCs, indicating that Ihh stimulates Gli-I-dependent signaling pathway in PSCs. Unexpectedly, however, adenovirus-mediated Gli-I overexpression blocked the Inn enhancement of both MTI-MMP localization on the plasma membrane and PSC migration. Furthermore, reduction of Gli-I expression with RNA interference augmented lhh-stimulated PSC migration. These data indicate that lhh promotes PSC migration by enhancing MTI-MMP localization on the plasma membrane but is negatively regulated by Gli-I.