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Pancreatic Stellate Cells in Health and Disease Pancreatic Stellate Cells in Health and Disease Alpha R. Mekapogu, Srinivasa P. Pothula, Romano C. Pirola, Jeremy S. Wilson, Minoti V. Apte Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Ingham Institute for Applied Medical Research, Sydney, Australia e-mail: [email protected]. Version 1.0, November 17th, 2020 [DOI: 10.3998/panc.2020.08] Abstract the pancreas – chronic pancreatitis and pancreatic cancer. In health, the process of fibrogenesis is a Pancreatic stellate cells (PSCs) are resident cells well-regulated dynamic process which is of the pancreas, found in both the exocrine and necessary for regular turnover of extracellular endocrine parts of the gland. Over the two decades matrix (ECM) that allows remodeling and since these cells were first isolated and cultured maintenance of normal pancreatic architecture. from rodent and human pancreas, research in this However, during injury, the equilibrium between area has progressed at a rapid rate. Our production and degradation of fibrous tissue is knowledge of PSC biology in both health and disrupted leading to excessive deposition of disease has increased significantly. In health, extracellular matrix proteins resulting in fibrosis. PSCs are known to not only play a role in regulating normal extracellular matrix turnover but Pancreatic stellate cells (PSCs) are now are also thought to have progenitor cell functions considered to be the key contributors of pancreatic as well as a role in innate immunity. The critical fibrosis (5, 11, 135). These cells were first roles of PSCs in inflammatory as well as malignant observed by Watari et al. (144) in 1982, and later disease of the pancreas are now being increasingly confirmed by Ikejiri (54) in 1990. The development elucidated. An improved understanding of PSC of isolation and culture methods for PSCs in 1998 biology and of the interactions of PSCs with other helped to unravel the mechanisms involved in the pancreatic cells provides a strong platform for the process of pancreatic fibrogenesis (5, 11) and also development of novel therapeutic approaches for helped researchers to investigate the functions of notoriously hard to treat diseases of the pancreas these cells both in health and disease. such as chronic pancreatitis and pancreatic cancer. II. PANCREATIC STELLATE CELLS (PSCs) I. INTRODUCTION A. PSCs in health Pancreatic fibrosis is a well-recognized histopathological feature of two major diseases of In a healthy pancreas, PSCs make up 4-7% (5) of the total parenchyma and are located around the 1 basolateral aspects of the acinar cells (Figure 1A). activation compared to PSCs. Upon activation, PSCs are also found around small pancreatic ducts they express more α-SMA but have reduced rates (5, 11), pancreatic islets (163) and blood vessels. of proliferation and migration compared to exocrine PSCs in their native state express abundant PSCs (163). vitamin A (retinoids) containing droplets in their cytoplasm which is a characteristic feature of the PSCs are the primary producers of ECM proteins “stellate cell system” in the body (138). The such as collagen I–IV, fibronectin, and laminin. At buoyancy imparted by the vitamin A containing the same time, they also produce ECM degrading vesicles was utilized by Apte et al. (5) to develop a enzymes like matrix metalloproteinases (MMP) density gradient centrifugation method for the and their inhibitors - tissue inhibitors of matrix isolation of quiescent PSCs from the pancreas. In metalloproteinases (TIMPs) (101). In the normal early culture, PSCs are polygonal in shape with pancreas, these enzymes maintain an equilibrium abundant lipid droplets in the cytoplasm (Figure between the deposition and degradation of ECM 1B) and express stellate cell selective markers proteins. However, it is now recognised that PSCs such as desmin, glial fibrillary acidic protein have functions beyond ECM remodeling in the (GFAP), nestin, neural cell adhesion molecule, normal pancreas. PSCs express receptors for the nerve growth factor, and synemin (34, 167). Due to secretagogue cholecystokinin (CCK1 and CCK2) the expression of neural markers, PSCs were (14) and have the capacity to synthesize the initially thought to be of neuroectodermal origin. neurotransmitter acetylcholine (ACh). However, lineage tracing studies with hepatic Upon exposure to physiological levels of CCK, stellate cells (counterparts of PSCs in the liver) PSCs have been shown to secrete ACh which, in have confirmed a mesenchymal origin for these turn, acts on the muscarinic receptors on acinar cells (9). The fact that a proportion of PSCs are cells and induces amylase secretion. (102). PSCs replenished from bone marrow further supports a also play an important role in innate immunity mesenchymal origin for PSCs (120). through the expression of Toll-like receptors (TLRs) 2, 3, 4 and 5 (78) which can recognise pathogen-associated molecular patterns (PAMPs), alarmins and endogenous molecules released by tissue damage (DAMPs). These cells also possess the ability to phagocytose polymorphonuclear neutrophils and cell debris, which is mediated by CD36 via peroxisome proliferator-activated Figure 1. (A) Normal rat pancreatic stellate cells receptor γ (116). PSCs may also possess stained for cytoskeletal protein desmin. progenitor-like capabilities since they express Photomicrograph showing a normal rat pancreatic section immunostained for the stellate cell selective several stem cell markers, including CD133, marker desmin (left) and a corresponding line diagram SOX9, nestin, and GDF3 (64, 83). They can (right). Desmin-positive (brown) PSCs can be seen differentiate into other cell types including insulin- surrounding the basolateral aspects of pancreatic acini. secreting cells under the influence of relevant (B) PSCs in an early culture showing a typical flattened polygonal shape with abundant vitamin A-containing growth factors (14, 41, 83, 88, 118). lipid droplets in the cytoplasm. Source: Apte et al. 1998 (5). (Reproduced with permission from BMJ Publishing B. PSCs in disease Group Ltd.). In the event of pancreatic injury, PSCs are Islet stellate cells (ISCs) are similar to but differ in activated, leading to loss of the vitamin A- certain aspects with PSCs. ISCs have fewer containing lipid droplets and transform to a vitamin-A containing droplets and undergo rapid myofibroblast-like phenotype that expresses alpha 2 smooth muscle actin (αSMA), fibroblast activation of sustaining their own activation (even in the protein-α (FAP-α), fibroblast specific protein-1 absence of the initial triggers) through the (FSP-1), and fibrinogen (34). These cells also production of cytokines such as (transforming exhibit increased proliferation, migration, and ECM growth factor beta [TGFβ], connective tissue synthesis (4, 44). Activated PSCs produce growth factor [CTGF], interleukins 6, 7, 8 and 15, collagenous stroma during pancreatic injury (8, CXCR1, monocyte chemotactic protein 1 [MCP1], 145, 152) which overwhelms the ECM degrading and regulated-on- activation- normal T-cell capacity of MMPs, leading to fibrosis. A expressed-and-secreted [RANTES]) (2, 57, 112). comparison of resting and activated PSCs is given These cytokines act via corresponding receptors in Table 1. on the PSCs themselves (autocrine effects) leading to a state of perpetual activation, which further facilitates pathological fibrosis. Several pathways that mediate PSC activation have now been identified (summarized in Table 3). A number of these pathways interact with each other leading to significant redundancy in terms of the modulation of PSC activation (81, 85). Furthermore, studies have also shown that PSCs can be activated by several factors such as numerous signaling pathways can converge proinflammatory cytokines (87), oxidant stress (20, causing aberration of a common secondary 130), ethanol and its metabolites, acetaldehyde messenger, namely, sustained increase in and fatty acid ethyl esters (3, 80), fatty acids intracellular calcium within the PSCs (42, 48, 147). (oleate) (13) and endotoxins (137) (Table 2). In Recently microRNAs, (small noncoding RNAs), addition, in the setting of pancreatic cancer, factors which are implicated in cell functions such as such as acidosis (142), hypoxia (77), increased proliferation, differentiation, apoptosis, and protein interstitial pressure (105) and hyperglycemia (92) synthesis, have been shown to differentially are also involved in the activation of PSCs. express between quiescent and activated PSCs Recently, epigenetic modifications (increased (79). Other studies have implicated miR15b and 16 acetylation of histones) have also been shown to (known to regulate PSC apoptosis (113) and play an important role in the activation of PSCs and miR21 as possible cofactors in connective tissue collagen synthesis (65). In addition to being growth factor (CCN2)-mediated PSC activation activated by exogenous factors, PSCs are capable (22). 3 Table 3. Signalling pathways involved in the interactions between PSCs and cancer cells. α-SMA, alpha smooth muscle actin; c-MET, tyrosine-protein kinase of Met; CCL, chemokine ligand; CXCL, chemotactic cytokine ligand; ECM, extracellular matrix; JAK/STAT, Janus kinase/signal transducers and activators of transcription; HGF, hepatocyte growth factor; PSC, pancreatic stellate cells; PCC, pancreatic cancer cells; SDF, stromal derived factor; PDGF, platelet-derived growth factor; SMAD, small worm mothers against decapentaplegic.
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