scholarly journals Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis

Gut ◽  
1999 ◽  
Vol 44 (4) ◽  
pp. 534-541 ◽  
Author(s):  
M V Apte ◽  
P S Haber ◽  
S J Darby ◽  
S C Rodgers ◽  
G W McCaughan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Collagen Synthesis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Oxidant Stress ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Cell Counts ◽  
Ecm Proteins

BACKGROUNDThe pathogenesis of pancreatic fibrosis is unknown. In the liver, stellate cells play a major role in fibrogenesis by synthesising increased amounts of collagen and other extracellular matrix (ECM) proteins when activated by profibrogenic mediators such as cytokines and oxidant stress.AIMSTo determine whether cultured rat pancreatic stellate cells produce collagen and other ECM proteins, and exhibit signs of activation when exposed to the cytokines platelet derived growth factor (PDGF) or transforming growth factor β (TGF-β).METHODSCultured pancreatic stellate cells were immunostained for the ECM proteins procollagen III, collagen I, laminin, and fibronectin using specific polyclonal antibodies. For cytokine studies, triplicate wells of cells were incubated with increasing concentrations of PDGF or TGF-β.RESULTSCultured pancreatic stellate cells stained strongly positive for all ECM proteins tested. Incubation of cells with 1, 5, and 10 ng/ml PDGF led to a significant dose related increase in cell counts as well as in the incorporation of3H-thymidine into DNA. Stellate cells exposed to 0.25, 0.5, and 1 ng/ml TGF-β showed a dose dependent increase in α smooth muscle actin expression and increased collagen synthesis. In addition, TGF-β increased the expression of PDGF receptors on stellate cells.CONCLUSIONSPancreatic stellate cells produce collagen and other extracellular matrix proteins, and respond to the cytokines PDGF and TGF-β by increased proliferation and increased collagen synthesis. These results suggest an important role for stellate cells in pancreatic fibrogenesis.

scholarly journals BMP2 inhibits TGF-β-induced pancreatic stellate cell activation and extracellular matrix formation

2013 ◽  
Vol 304 (9) ◽  
pp. G804-G813 ◽  
Author(s):  
Xuxia Gao ◽  
Yanna Cao ◽  
Wenli Yang ◽  
Chaojun Duan ◽  
Judith F. Aronson ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Steady Increase ◽  
Pathological Feature

Activation of pancreatic stellate cells (PSCs) by transforming growth factor (TGF)-β is the key step in the development of pancreatic fibrosis, a common pathological feature of chronic pancreatitis (CP). Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have anti-fibrogenic functions, in contrast to TGF-β, in the kidney, lung, and liver. However, it is not known whether BMPs have an anti-fibrogenic role in the pancreas. The current study was designed to investigate the potential anti-fibrogenic role of BMPs in the pancreas using an in vivo CP model and an in vitro PSC model. CP was induced by repetitive intraperitoneal injections of cerulein in adult Swiss Webster mice. The control mice received saline injections. Compared with the control, cerulein injections induced a time-dependent increase in acinar injury and progression of fibrosis and a steady increase in inflammation. Cerulein injections also induced increases of the extracellular matrix (ECM) protein fibronectin and of α-smooth muscle actin (α-SMA)-positive stellate cells (PSCs). The mice receiving cerulein injections showed increased BMP2 protein levels and phosphorylated Smad1 levels up to 4 wk and then declined at 8 wk to similar levels as the control. In vitro, the isolated mouse and human PSCs were cultured and pretreated with BMP2 followed by TGF-β treatment. BMP2 pretreatment inhibited TGF-β-induced α-SMA, fibronectin, and collagen type Ia expression. Knocking down Smad1 with small-interfering RNA reversed the inhibitory effect of BMP2 on TGF-β-induced α-SMA and fibronectin expression. Thus, BMP2 opposes the fibrogenic function of TGF-β in PSCs through the Smad1 signaling pathway.

scholarly journals New aspects of formation and progression of pancreatic fibrosis in pancreatitis

2019 ◽  
Vol 43 (2) ◽  
pp. 20-24
Author(s):  
V. A. Akhmedov ◽  
O. V. Gaus
Keyword(s):  
Extracellular Matrix ◽  
Chronic Pancreatitis ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Stellate Cells ◽  
Transforming Growth Factor Β ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Main Components ◽  
Acute And Chronic Pancreatitis

Fibrosis formation is a dynamic process during which the formation of an extracellular matrix takes place in interstitial spaces and areas where the main components of exocrine pancreatic function (acinar cells) are damaged. According to studies, the biggest role in the formation of pancreatic fibrosis upon chronic pancreatitis is played by various types of effector cells, such as fibroblasts, myofibroblasts and fibrocytes, while fibroblasts and myofibroblasts are the key fibrosis cells responsible for the secretion of extracellular matrix. Activated pancreatic stellate cells become main components of fibrosis formation in patients with chronic pancreatitis, synthesizing transforming growth factor-β, fibroblast growth factor, which leads to enhanced synthesis of extracellular matrix. The presented review highlights molecular mechanisms (Rho-kinase, mitogen-activating protein kinase, transforming growth factor-β, associated with the protein encoded by SMAD in humans, phosphatidylinositol-3 kinase), which play an important role in the activation of pancreatic stellate cells and launching the phenomenon of pancreatic fibrogenesis. The presented data opens up prospects for the development of diagnostic areas with the search for new markers for the diagnosis of acute and chronic pancreatitis along with development of new therapeutic options for the pathogenetic therapy of patients with acute and chronic pancreatitis based on the results obtained.

scholarly journals HDGF supports anti-apoptosis and pro-fibrosis in pancreatic stellate cells of pancreatic cancer

2018 ◽  
Author(s):  
Yi-Ting Chen ◽  
Tso-Wen Wang ◽  
Tsung-Hao Chang ◽  
Teng-Po Hsu ◽  
Jhih-Ying Chi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor ◽  
Cancer Cells ◽  
Transforming Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Stellate Cells ◽  
Transforming Growth Factor Β1 ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Cancer Cells ◽  
Tgf Β1

ABSTRACTPancreatic cancer is refractory and characterized by extensively surrounding- and intra-tumor fibrotic reactions that are contributed by activated pancreatic stellate cells (PSCs). Activation of PSCs plays a pivotal role for developing fibrotic reactions to affect themselves or pancreatic cancer cells (PCCs). In the current study, we demonstrated that hepatoma-derived growth factor (HDGF) was secreted from transforming growth factor-β1 (TGF-β1)-treated PSCs. We found that HDGF contributed to anti-apoptosis of PSCs and led to synthesis and depositions of extracellular matrix proteins for stabilizing PSCs/PCCs tumor foci. CCAAT/enhancer binding protein δ (CEBPD) responds to TGF-β1 through a reciprocal loop regulation and further activated hypoxia inducible factor-1α (HIF-1α) contributed to up-regulation ofHDGFgene. It agrees with the observation that severe stromal growth positively correlated with stromal HDGF and CEBPD in pancreatic cancer specimens. Collectively, the identification of TGF-β1-activated CEBPD/HIF-1α/HDGF axis provides new insights for the novel discoveries of HDGF in anti-apoptosis and pro-fibrosis of PSCs and outgrowth of pancreatic cancer cells.

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