Roles of Pancreatic Stellate Cells in Pancreatic Inflammation and Fibrosis

doi:10.1016/j.cgh.2009.07.038

Clinical Gastroenterology and Hepatology

Volume 7, Issue 11, Supplement, November 2009, Pages S48-S54

https://doi.org/10.1016/j.cgh.2009.07.038 Get rights and content

Over a decade, there is accumulating evidence that activated pancreatic stellate cells (PSCs) play a pivotal role in the development of pancreatic fibrosis. In response to pancreatic injury or inflammation, quiescent PSCs are transformed (activated) to myofibroblast-like cells, which express α-smooth muscle actin. Activated PSCs proliferate, migrate, produce extracellular matrix components, such as type I collagen, and express cytokines and chemokines. Recent studies have suggested novel roles of PSCs in local immune functions and angiogenesis in the pancreas. If the pancreatic inflammation and injury are sustained or repeated, PSC activation is perpetuated, leading to the development of pancreatic fibrosis. In this context, pancreatic fibrosis can be defined as pathologic changes of extracellular matrix composition in both quantity and quality, resulting from perpetuated activation of PSCs. Because PSCs are very similar to hepatic stellate cells, PSC research should develop in directions more relevant to the pathophysiology of the pancreas, for example, issues related to trypsin, non-oxidative alcohol metabolites, and pancreatic cancer. Indeed, in addition to their roles in chronic pancreatitis, it has been increasingly recognized that PSCs contribute to the progression of pancreatic cancer. Very recently, contribution of bone marrow–derived cells to PSCs was reported. Further elucidation of the roles of PSCs in pancreatic fibrosis should promote development of rational approaches for the treatment of chronic pancreatitis and pancreatic cancer.

Section snippets

Activation of Pancreatic Stellate Cells

In normal pancreas, stellate cells are quiescent and can be identified by the presence of vitamin A–containing lipid droplets in the cytoplasm.1, 2, 3, 4, 5 PSCs show mainly a periacinar distribution and constitute 4% of all pancreatic cells.1, 2 Expression of the intermediate filament proteins, desmin and glial fibrillary acidic protein (GFAP), is also used as a marker of quiescent PSCs. The expression and activation of GFAP have been confirmed in transgenic GFAP-LacZ mice where 2.2 kilobase

Functions of Pancreatic Stellate Cells

On activation, PSCs lose lipid droplets, more actively proliferate, migrate, produce ECM components, and secrete proinflammatory cytokines and chemokines.1, 2, 3, 4, 5, 6, 7, 8, 19 Cytokines and growth factors produced by acinar cells, inflammatory cells, platelets, ductal cells, endothelial cells, cancer cells, and PSCs by themselves could activate PSCs and induce these cell responses in paracrine and autocrine manners.1, 2, 3, 4, 5, 6, 7, 8 Accumulating evidence supports major roles for PDGF,

Postactivation Events

After the initiation of activation, PSCs might have 2 fates (Figure 3). If the inflammation and injury are sustained or repeated, PSC activation is perpetuated, leading to the development of pancreatic fibrosis. By contrast, if the inflammation and injury are limited, PSCs might undergo apoptosis or revert to quiescence. In this case, fibrosis will not develop. From this point of view, pancreatic fibrosis can be defined as pathologic changes of ECM composition in the pancreas in both quantity

Interaction Between Pancreatic Stellate Cells and Cancer Cells

Because PSCs are morphologically and functionally very similar to hepatic stellate cells, the major effector cells in liver fibrosis, it is particularly interesting to see whether the 2 populations differ in content or function. DNA array study showed that only 29 of 23,000 genes (0.1%) were different between PSCs and hepatic stellate cells.³⁵ It would seem that research of PSCs should develop in directions more relevant to the pathophysiology of the pancreas, for example, responses to trypsin,

Origin of Pancreatic Stellate Cells

Although PSCs and hepatic stellate cells might exhibit functional differences, the 99.9% identity at the mRNA level suggests that PSCs and hepatic stellate cells might have a common origin. Activated PSCs have been thought to arise from transformation of quiescent PSCs that reside in the pancreas.1, 2, 3, 4, 5 However, studies with sex-mismatched bone marrow (BM) transplantation from a transgenic male mouse carrying enhanced green fluorescent protein to female wild-type mice suggested that

Antifibrosis Therapies Targeting Pancreatic Stellate Cells

Because activated PSCs play a pivotal role in the development of pancreatic fibrosis, factors that control their cellular functions could provide potential targets for the treatment of pancreatic fibrosis and inflammation.⁴⁷ Antifibrosis treatment strategies that target PSCs include (1) inhibiting activation of quiescent PSCs, (2) controlling cell functions in PSCs, (3) anti-cytokine and anti–growth factor therapies, (4) induction of apoptosis and reversion to quiescence in PSCs, and (5)

Concluding Remarks

Pancreatic fibrosis can be defined as pathologic changes of ECM composition in both quantity and quality, resulting from perpetual activation of PSCs. In addition to their roles in CP, it is increasingly recognized that PSCs contribute to the progression of pancreatic cancer. In this context, a major investigative goal will be to determine whether modulators of stellate cell activities can be developed that will prove useful for the treatment of pancreatic cancer as well as of CP.

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: Conflicts of interest The authors disclose no conflicts.

: Funding Supported in part by Grant-in-Aid from Japan Society for the Promotion of Science (A.M.), by the Pancreas Research Foundation of Japan (A.M.), by the Kanae Foundation for Life and Socio-Medical Science (A.M.), by the Uehara Memorial Foundation (A.M.), and by the Research Committee of Intractable Pancreatic Diseases (Principal investigator, T.S.) provided by the Ministry of Health, Labour, and Welfare of Japan.

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Roles of Pancreatic Stellate Cells in Pancreatic Inflammation and Fibrosis

Section snippets

Activation of Pancreatic Stellate Cells

Functions of Pancreatic Stellate Cells

Postactivation Events

Interaction Between Pancreatic Stellate Cells and Cancer Cells

Origin of Pancreatic Stellate Cells

Antifibrosis Therapies Targeting Pancreatic Stellate Cells

Concluding Remarks

Gastroenterology

Gastroenterology

Dig Liver Dis

Lab Invest

Gastroenterology

Gastroenterology

J Biol Chem

Gastroenterology

Gastroenterology

Gastroenterology

Biochem Biophys Res Commun

Gastroenterology

Gastroenterology

Curr Opin Cell Biol

Gastroenterology

Lab Invest

Biochem Pharmacol

Periacinar stellate-shaped cells in rat pancreas: identification, isolation and culture

Gut

The pancreatic stellate cell: a star on the rise in pancreatic diseases

J Clin Invest

Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis

J Gastroenterol

Signal transduction in pancreatic stellate cells

J Gastroenterol

Cancer-associated stromal fibroblasts promote pancreatic tumor progression

Cancer Res

Pancreatic stellate cells: partners in crime with pancreatic cancer cells

Cancer Res

Vitamin A inhibits pancreatic stellate cell activation: implications for treatment of pancreatic fibrosis

Gut

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

Am J Physiol Cell Physiol

Pancreatic stellate cells respond to inflammatory cytokines: potential role in chronic pancreatitis

Gut

Activin A is an autocrine activator of rat pancreatic stellate cells: potential therapeutic role of follistatin for pancreatic fibrosis

Gut