AbstractsMedical & Health Science

Pancreatic stellate cells in chronic pancreatitis

by Lu Yang

Institution: University of New South Wales
Department: Clinical School - South Western Sydney
Year: 2011
Keywords: Microarray; Pancreatic stellate cells; Chronic pancreatitis
Record ID: 1042988
Full text PDF: http://handle.unsw.edu.au/1959.4/51672


It is now generally accepted that activated pancreatic stellate cells (PSCs) are the principal effector cells in pancreatic fibrosis, a characteristic histological feature of chronic pancreatitis. PSC activation is associated with loss of cytoplasmic vitamin A containing lipid droplets, expression of cytoskeletal protein alpha-smooth muscle actin (αSMA), increased proliferation, and synthesis and secretion of extracellular matrix (ECM) proteins (the latter, in turn, influence gene expression patterns of PSCs during the activation process). One of the leading causes of chronic pancreatitis is alcohol abuse and in vitro studies have established that alcohol and cytokines (known to be released during pancreatic necroinflammation) can individually activate PSCs. However, during alcohol-induced pancreatic injury, PSCs are likely to be exposed to a combination of ethanol and cytokines (rather than individual factors). Therefore, aims of this study were 1) to investigate the combined effects of ethanol and cytokines on PSCs; 2) to assess and compare gene expression profiles of PSCs cultured on matrices that mimick normal and diseased pancreas - MatrigelTM and collagen I, respectively; 3) to validate and study the influence of selected genes (e.g. transgelin) on PSC activation. Results of this study demonstrated that i) at low doses, ethanol (5mM), IL-1 (0.5pg/mL) or TNFα (10U/mL) alone have negligible effects on PSC activation. However, PSCs treated with a combination of ethanol and cytokines exhibit significantly increased activation; ii) in PSCs cultured on different matrices (MatrigelTM, collagen I and plastic) several genes are dysregulated (fold change>2, p<0.001 and q<0.25) as follows: a) PSCs on collagen I vs MatrigelTM 146 dysregulated genes (76↓, 70↑); b) PSCs on matrigel vs plastic 619 dysregulated genes (297↓, 322↑); and c) PSCs on collagen I vs plastic 432 dysregulated genes (178↓, 254↑); iii) selected genes (transgelin and lumican) are increased in PSCs cultured on fibrous ECM and are associated with PSC activation; iv) inhibition of transgelin expression in PSCs decreases cell proliferation. Thus, studies in this thesis have i) provided evidence in support of the hypothesis that PSCs can be activated synergistically by alcohol and cytokines, ii) shown that the gene expression profile of PSCs is altered by ECM components during PSC activation and; iii) identified a possible molecular target specific for PSCs in the diseased pancreas.