Pancreatic stellate cell

Pancreatic stellate cells (PaSCs) are classified as myofibroblast-like cells that are located in exocrine regions of the pancreas. PaSCs are mediated by paracrine and autocrine stimuli and share similarities with the hepatic stellate cell. Pancreatic stellate cell activation and expression of matrix molecules constitute the complex process that induces pancreatic fibrosis. Synthesis, deposition, maturation and remodeling of the fibrous connective tissue can be protective, however when persistent it impedes regular pancreatic function.

Structure PaSCs are located within the peri-acinar spaces of the pancreas and extrude long cytoplasmic processes that surround the base of the acinus. PaSCs compose 4% of the total cell mass in the gland. Stellate cells derive their name from their star shape and are located in other organs such as the kidney and lungs. The cells are located in periductal and perivascular regions of the pancreas and contain vitamin A lipid droplets in their cytoplasm. PaSCs engage in disease pathogenesis by transforming from a quiescent state into an activated state, which is also known as a “myofibroblastic” state. PaSCs express the intermediate filament proteins desmin and glial fibrillary acidic protein. The expression of a diverse range of intermediate filament proteins enables the PaSC to harbour contractile abilities. Cellular extensions also enable the cells to sense their environment. Following inflammation or injury to the pancreas, quiescent PaSCs are activated to myofibroblast-like cells, which express α-smooth muscle actin. Several morphological changes take place including nuclear enlargement and increased growth of the endoplasmic reticulum network. The activated PaSCs then grow in number, migrate and secrete extracellular matrix components such as type I collagen, chemokines and cytokines.

Function Quiescent PaSCs produce metalloproteinases such as MMP-2, MMP-9, and MMP-13 and their inhibitors, which assist in the turnover of the extracellular matrix (ECM). As a result of regulating ECM turnover, PaSCs are involved in the maintenance of the modelling of normal tissue. MMP-2 secreted by PaSCs, however, contributes to the development of pancreatic cancer. Fibrosis is a prominent feature of chronic pancreatitis and of the desmoplastic reaction linked with pancreatic cancer. While the pathogenesis of fibrosis remains elusive, the activation of stellate cells contribute to pancreatic fibrosis. Numerous soluble factors regulate PaSC activation, specifically IL-1, IL-6, TNF-α, TGF-B1 and activin 1. The potential sources of these activating factors include platelets, macrophages, pancreatic acinar cells and endothelial cells in inflamed pancreas. PaSCs, individually, are also capable of synthesising cytokines such as TGF-β1, activin A and IL-1. The production of these factors indicates the presence of autocrine loops that perpetuate PaSC activation, promoting the development of fibrosis. Protein kinases such as mitogen-activated protein kinases (MAPKs) are primary mediators of activating signals initiated by the growth factors, angiotensin II and ethanol. Other signalling pathways regulating PaSC activation include PI3K, RHO kinase and TGF-β/SMAD-related pathways. Following activation, PaSCs migrate to areas of tissue damage and contract, phagocytose, and induce products that regulate the ECM through facilitating repair or by promoting fibrosis. The migration of PaSCs is modulated by Indian hedgehog (IHH), a peptide that is involved in pancreatic development, patterning and differentiation. Stellate cells express smoothened (Smo) and patched-1 (Ptch1) proteins, which are significant features of the hedgehog receptor system. Indian Hedgehog binding results in relocation of the transcriptional of transcription factor Gli-1 into the nucleus, inducing chemokinetic migration of PaSCs. Following activation, PaSCs have two fates. If there is sustained inflammation and injury, PaSC activation is perpetuated, resulting in the growth of pancreatic fibrosis. The activation of P2 receptors induces intracellular calcium signalling which mediates the fibrogenic function of activated stellate cells. However, if inflammation and injury is minor, PaSCs undergo an apoptotic fate and become quiescent, preventing the development of fibrosis. PaSCs also display ethanol-inducible alcohol dehydrogenase (ADH) activity. The possibility that pancreatic stellate cells may be exposed to ethanol and acetaldehyde during ethanol consumption is likely, as the pancreas metabolise ethanol to acetaldehyde through the oxidative pathway. PaSCs are activated upon exposure to ethanol and its metabolite acetaldehyde or to oxidant stress. Ethanol at clinically relevant concentrations causes α-SMA expression and collagen production in PaSCs but produce a minimal effect on cell proliferation. Increased α-SMA expression in stellate cells exposed to ethanol suggests activation and transformation of the cells to a myofibroblast phenotype. Incubation of PaSCs with ethanol in the presence of ADH inhibitor 4MP had inhibited the increase in collagen synthesis induced by ethanol. The conversion of ethanol to acetaldehyde via ADH is a significant step in the ethanol induced activation of pancreatic stellate cells.

Clinical significance

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