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Are we studying the correct state of the stellate cell to elucidate mechanisms of chronic pancreatitis?
  1. S J Pandol
  1. Correspondence to:
    Dr S Pandol
    UCLA Department of Medicine, West Los Angeles VAGLAHS, 11301 Wilshire Blvd., Building 258, Room 340, Los Angeles, CA 90073, USA; stephen.pandol{at}med.va.gov

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Important insights into the states of pancreatic stellate cells and their relation to the disease conditions of the pancreas

The processes of chronic pancreatitis include chronic inflammation and fibrosis with loss of parenchymal cells of the exocrine and endocrine pancreas. These processes lead to irreversible and debilitating exocrine and endocrine insufficiency and a severe chronic pain syndrome. Although elucidation of the mechanisms underlying chronic pancreatitis are incomplete, considerable progress has been made in our understanding of the fibrosis process as a result of identification and characterisation of pancreatic stellate cells (PSCs) starting in 1997.1–3 Studies with these cells suggest that they play a key role in chronic pancreatitis in a manner analogous to hepatic stellate cells and hepatic fibrosis4,5

In common with liver fibrosis and hepatic stellate cells there is increasing evidence demonstrating a central role for PSCs in pancreatic fibrosis and chronic pancreatitis. In the normal pancreas, quiescent PSCs are identified using antibodies to desmin, a cytoskeletal protein and specific PSC marker.1 They are present in the periacinar space with long cytoplasmic processes encircling the base of the acinus. Similar to hepatic stellate cells in their quiescent state, PSCs store significant amounts of vitamin A as lipid droplets in their cytoplasm.

There is general acceptance that during pancreatic injury PSCs are activated in a manner similar to hepatic stellate cells. Activation consists of processes of transformation to a myofibroblastic phenotype with loss of vitamin A stores and expression of the cytoskeletal protein α smooth muscle actin (α-SMA); production and secretion of large amounts of extracellular matrix proteins, including collagen, fibronectin, and laminin.6 Activation can be mediated by cytokines such as transforming growth factor β and platelet derived growth factor.2 These agents can be produced and secreted by pancreatic parenchymal cells, inflammatory cells, and PSCs themselves.7,8 These effects of the stellate cells to produce growth factors and inflammatory mediators can be responsible for autocrine mediated proliferation and activation of stellate cells as well as for the chronic inflammatory response in chronic pancreatitis. These responses of the stellate cell may account for the continued progression of chronic pancreatitis processes in individuals, even after cessation of alcohol abuse.

Support for PSCs in the pathogenesis of pancreatic fibrosis in chronic pancreatitis comes from investigations of pancreatic tissue in patients with chronic pancreatitis and from animal experimental models.9,10 The results demonstrated that in both situations PSCs, as identified by α-SMA actin antibodies, are present in fibrotic areas, as determined by Sirius red or collagen I antibody staining. Furthermore, α-SMA positive cells also stained by in situ hybridisation with a probe for collagen α1 mRNA, indicating that these cells are an important source of collagen in fibrotic areas. Such findings provide strong evidence for PSCs in the mechanism of pancreatic fibrosis.

Because of the key role for the stellate cell in the mechanism of these chronic inflammatory/fibrosing states, elucidation of the mechanisms of its transformation is necessary in order to develop treatment strategies. One of the major dilemmas in the research of stellate cells is the fact that they undergo transformation to an activated phenotype after isolation during in vitro culture. Do cultured stellate cells undergoing transformation in vitro represent the state of the stellate cell in chronic fibrosing diseases of the pancreas? Is this the correct state of the PSC to study for determining its role in chronic fibrosing disease? These questions have not been adequately addressed.

The paper by Manapov and colleagues11 in this issue of Gut provides important insights into the states of PSCs and their relation to the disease conditions of the pancreas (see page 814). The key findings in this study are that stellate cells undergoing activation in culture can either die by apoptosis or convert to “fibroblasts” that are resistant to apoptosis. Furthermore, the authors found that the phenotype of activated stellate cells susceptible to apoptosis occurs in an experimental model of pancreatitis that resolves with return of the pancreas to normal after removal of the injury. On the other hand, cells with the “fibroblast” phenotype are present in an experimental model of progressive pancreatic fibrosis. The authors demonstrated that in the activated stellate cell susceptible to apoptosis, a cell cycle inhibitory protein p21Cip1/WAF1 is present in the nucleus. With conversion of the stellate cell to the “fibroblastic” state, p21Cip1/WAF1 translocates to the cytoplasm. Cytoplasmic p21Cip1/WAF1 binds to and inhibits activities of Rho kinase 2 and apoptosis signal regulating kinase 1, resulting in decreased proliferation signals and apoptosis resistance.

Of interest, α-SMA, a marker of activation in stellate cells, is reduced in expression in “fibroblastic” cells. Thus although α-SMA is a frequently used measure of the activated state of stellate cells, it may not identify the cell population responsible for fibrosis. Findings that non-α-SMA expressing fibroblastic cells are responsible for both pancreatic and hepatic fibrosis have been reported in experimental models of pancreatitis and human cirrhosis.12,13

What is the significance of the findings related to p21Cip1/WAF1? This cell cycle inhibitory protein may represent a central regulator of terminal differentiation, as shown in monocytic and neural cells.14,15 In these cases, p21Cip1/WAF1 expression with localisation in the nucleus leads to cell cycle arrest followed by its translocation to the cytoplasm where it is associated with terminal differentiation. Translocation of p21Cip1/WAF1 to the cytoplasm in these cells also results in apoptosis resistance, as occurred in the stellate cells.

Considering the similarities in the pattern of changes in p21Cip1/WAF1 associated with differentiation in monocytic cells, neuronal cells, and stellate cells, the results in the report by Manapov and colleagues11 provides a basis to propose that the “fibroblastic” phenotype of the stellate cell is a terminally differentiated state. As described in this report and previous ones,13,14 this phenotype expresses little or no α-SMA and is resistant to apoptosis. Furthermore, it is very likely, as proposed by Manapov et al, that p21Cip1/WAF1 plays a central role in proliferation, apoptosis, and differentiation of the stellate cell. The mechanisms underlying regulation of p21Cip1/WAF1 expression and translocation are unknown. Establishing the underlying mechanism for one or both of these processes may lead to potential strategies for the treatment of fibrosing diseases.

Important insights into the states of pancreatic stellate cells and their relation to the disease conditions of the pancreas

REFERENCES

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Footnotes

  • Conflict of interest: None declared.

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