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Am J Physiol Cell Physiol 281: C532-C543, 2001;
0363-6143/01 $5.00
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Vol. 281, Issue 2, C532-C543, August 2001

Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells

Eric Schneider1,2,*, Alexandra Schmid-Kotsas1,*, Jinshun Zhao1, Hans Weidenbach2, Roland M. Schmid2, Andre Menke2, Guido Adler2, Johannes Waltenberger3, Adolf Grünert1, and Max G. Bachem1

Departments of 1 Clinical Chemistry and Pathobiochemistry, 2 Internal Medicine I, and 3 Internal Medicine II, University of Ulm, 89070 Ulm, Germany

The aim of this study was to identify fibrogenic mediators stimulating activation, proliferation, and/or matrix synthesis of rat pancreatic stellate cells (PSC). PSC were isolated from the pancreas of normal Wistar rats and from rats with cerulein pancreatitis. Cell activation was demonstrated by immunofluorescence microscopy of smooth muscle alpha -actin (SMA) and real-time quantitative RT-PCR of SMA, fibronectin, and transforming growth factor (TGF)-beta 1. Proliferation was measured by bromodeoxyuridine incorporation. Matrix synthesis was demonstrated on the protein and mRNA level. Within a few days in primary culture, PSC changed their phenotype from fat-storing to SMA-positive myofibroblast-like cells expressing platelet-derived growth factor (PDGF) alpha - and PDGF beta -receptors. TGF-beta 1 and tumor necrosis factor (TNF)-alpha accelerated the change in the cells' phenotype. Addition of 50 ng/ml PDGF and 5 ng/ml basic fibroblast growth factor (bFGF) to cultured PSC significantly stimulated cell proliferation (4.37 ± 0.49- and 2.96 ± 0.39-fold of control). Fibronectin synthesis calculated on the basis of DNA was stimulated by 5 ng/ml bFGF (3.44 ± 1.13-fold), 5 ng/ml TGF-beta 1 (2.46 ± 0.89-fold), 20 ng/ml PDGF (2.27 ± 0.68-fold), and 50 ng/ml TGF-alpha (1.87 ± 0.19-fold). As shown by RT-PCR, PSC express predominantly the splice variant EIII-A of fibronectin. Immunofluorescence microscopy and Northern blot confirmed that in particular bFGF and TGF-beta 1 stimulated the synthesis of fibronectin and collagens type I and III. In conclusion, our data demonstrate that 1) TGF-beta 1 and TNF-alpha accelerate the change in the cell phenotype, 2) PDGF represents the most effective mitogen, and 3) bFGF, TGF-beta 1, PDGF, and, to a lesser extent, TGF-alpha stimulate extracellular matrix synthesis of cultured rat PSC.

pancreas fibrosis; growth factors; fibrogenic mediators; collagen; fibronectin

* E. Schneider and A. Schmid-Kotsas contributed equally to this work.




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