Platelet-derived growth factors stimulate proliferation and extracellular matrix synthesis of pancreatic stellate cells: Implications in pathogenesisof pancreas fibrosis

At present, the cell-cell interactions and molecular mechanisms of pancreas fibrogenesis are largely unknown. The purpose of this study was to investi gate paracrine stimulatory loops between platelets and pancreatic stellate cells (PSC). Human PSC were obtained by outgrowth from fibrotic human pancr eas. Native platelet lysate (nPL) and transiently acidified platelet lysate (aPL) were added to cultured PSC (passage 4 to 7) in the absence of serum. The synthesis of collagen types I and III and c-fibronectin (cFN) was demo nstrated on protein (immunofluorescence and quantitative immunoassay) and m RNA (Northern blot) level. Using sections of human pancreas with acute panc reatitis, platelet aggregates in capillaries were demonstrated by transmiss ion electron microscopy. nPL, and to an even greater extent aPL, significan tly increased the synthesis of collagen types I and III and of c-FN (120 mu l/ml aPL increased collagen type I concentration in PSC supernatants by 1. 99 +/- 0.17 times and c-FN of 2.49 +/- 0.28 times, mean +/- SD, n = 3). nPL and aPL also significantly stimulated cell proliferation (increased bromod eoxyuridine (BrdU) incorporation by 6.4 +/- 0.78 times and 10 +/- 0.29 time s, respectively). By preincubating aPL with transforming growth factor beta (TGF beta)- and platelet-derived growth factor (PDGF)-neutralizing antibod ies and the TGF beta-latency associated peptide, respectively, TGF beta 1 w as identified as the main mediator stimulating matrix synthesis and PDGF as the responsible mitogen. Our data demonstrate that platelets contain fibro genic mediators that stimulate proliferation (PDGF) and matrix synthesis (T GF beta 1) of cultured PSC. We suggest that platelets and PSC cooperate in the development of pancreas fibrosis.