title: Phenotypic changes in mouse pancreatic stellate cell Ca2+ signaling events following activation in culture and in a disease model of pancreatitis.
abstract: The specific characteristics of intracellular Ca 2+ signaling and the downstream consequences of these events were investigated in mouse pancreatic stellate cells (PSC) in culture and in situ using multiphoton microscopy in pancreatic lobules. PSC undergo a phenotypic transformation from a quiescent state to a myofibroblast-like phenotype in culture. This is believed to parallel the induction of an activated state observed in pancreatic disease such as chronic pancreatitis and pancreatic cancer. By day 7 in culture, the complement of cell surface receptors coupled to intracellular Ca 2+ signaling was shown to be markedly altered. Specifically, protease-activated receptors (PAR) 1 and 2, responsive to thrombin and trypsin, respectively, and platelet-derived growth factor (PDGF) receptors were expressed only in activated PSC (aPSC). PAR-1, ATP, and PDGF receptor activation resulted in prominent nuclear Ca 2+ signals. Nuclear Ca 2+ signals and aPSC proliferation were abolished by expression of parvalbumin targeted to the nucleus. In pancreatic lobules, PSC responded to agonists consistent with the presence of only quiescent PSC. aPSC were observed following induction of experimental pancreatitis. In contrast, in a mouse model of pancreatic disease harboring elevated K-Ras activity in acinar cells, aPSC were present under control conditions and their number greatly increased following induction of pancreatitis. These data are consistent with nuclear Ca 2+ signaling generated by agents such as trypsin and thrombin, likely present in the pancreas in disease states, resulting in proliferation of "primed" aPSC to contribute to the severity of pancreatic disease.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Jong Hak
authors.initials: JH
authors.lastname: Won
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Baoan
authors.initials: B
authors.lastname: Ji
authors.forename: Craig D
authors.initials: CD
authors.lastname: Logsdon
authors.forename: David I
authors.initials: DI
authors.lastname: Yule
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D002478:Cells, Cultured; D051379:Mice; D058954:Pancreatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D044463:Receptor, PAR-1 / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism
chemical_list: D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D011956:Receptors, Cell Surface