Pancreatic stellate cell
Pancreatic stellate cell | |
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Details | |
Location | Pancreas |
Identifiers | |
MeSH | D058954 |
Anatomical terms of microanatomy |
Pancreatic stellate cells (PaSCs) are classified as myofibroblast-like cells that are located in exocrine regions of the pancreas.[1] PaSCs are mediated by paracrine and autocrine stimuli and share similarities with the hepatic stellate cell.[1] Pancreatic stellate cell activation and expression of matrix molecules constitute the complex process that induces pancreatic fibrosis.[2] Synthesis, deposition, maturation and remodelling of the fibrous connective tissue can be protective, however when persistent it impedes regular pancreatic function.[2]
Structure
[edit]PaSCs are located within the peri-acinar spaces of the pancreas and extrude long cytoplasmic processes that surround the base of the acinus.[1] PaSCs compose 4% of the total cell mass in the gland [3] Stellate cells derive their name from their star shape and are located in other organs such as the kidney and lungs.[1] The cells are located in periductal and perivascular regions of the pancreas and contain vitamin A lipid droplets in their cytoplasm.[1] PaSCs engage in disease pathogenesis by transforming from a quiescent state into an activated state, which is also known as a “myofibroblastic” state.[1]
PaSCs express the intermediate filament proteins desmin and glial fibrillary acidic protein.[1] The expression of a diverse range of intermediate filament proteins enables the PaSC to harbour contractile abilities.[1] Cellular extensions also enable the cells to sense their environment.[1] Following inflammation or injury to the pancreas, quiescent PaSCs are activated to myofibroblast like cells, which expresses
Function
[edit]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).[4] As a result of regulating ECM turnover, PaSCs are involved in the maintenance of the modelling of normal tissue.[4] MMP-2 secreted by PaSCs, however, contributes to the development of pancreatic cancer.[5]
Fibrosis is a prominent feature of chronic pancreatitis and of the desmoplastic reaction linked with pancreatic cancer.[6] While the pathogenesis of fibrosis remains elusive, the activation of stellate cells contribute to pancreatic fibrosis.[7]
Numerous soluble factors regulate PaSC activation, specifically IL-1, IL-6, TNF-
Protein kinases such as MAPKs are primary mediators of activating signals initiated by the growth factors, angiotensin II and ethanol.[1] Other signalling pathways regulating PaSC activation include PI3K, RHO kinase and TGF-
Following activation, PaSCs have two fates.[6] If there is sustained inflammation and injury, PaSC activation is perpetuated, resulting in the growth of pancreatic fibrosis.[6] The activation of P2 receptors induces intracellular calcium signalling which mediates the fibrogenic function of activated stellate cells.[10] However, if inflammation and injury is minor, PaSCs undergo an apoptotic fate and become quiescent, preventing the development of fibrosis.[6]
PaSCs also display ethanol inducible ADH activity.[7] 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.[7] PaSCs are activated upon exposure to ethanol and its metabolite acetaldehyde or to oxidant stress.[7] Ethanol at clinically relevant concentrations causes
Increased
Clinical significance
[edit]Pancreatitis
[edit]Pancreatitis is generally classified into two forms, acute and chronic.[11] In acute pancreatitis, necroinflammation of the organ occurs, while chronic pancreatitis is distinguished by the progressive loss of endocrine and exocrine function.[11] After pancreatic damage occurs, pathologic events such as interstitial oedema, necrosis of parenchymal cells, activation and proliferation of PaSCs take place.[1] Inflammation and parenchymal necrosis precede PaSC activation.[1] Activated PaSCs are located in areas of major necrosis and inflammation that harbour cytokines, growth factors and reactive oxygen species.[1] Inflammatory processes are essential in contributing towards the activation of stellate cells.[1] Therefore, both autocrine and paracrine mediators are involved pancreatic stellate cell activation.[1]
Copious amounts of
In humans, persistent injury to the pancreas is linked with chronic alcohol use, pancreatic duct obstruction and genetic.[1] Chronic damage leads to the sustained activation of the active PaSC phenotype.[1] Diminished production of MMPs by PaSCs also contributes to the fibrotic phenotype.[1] Other factors may also drive the persistent activated state of PaSCs in the event of pancreatitis.[1] For example, PaSCs express protease activated receptor-2 (PAR-2), which is cleaved by trypsin to become active.[1] Active PAR-2 then instigates PaSC growth and collagen synthesis.[1]
Cancer
[edit]Pancreatic adenocarcinomas are recognised by tumour desmoplasia, distinguished by an increase in the connective tissue that surrounds the neoplasm.[1] Activated PaSCs in the tumour desmoplasia of human pancreatic cancers express
Pancreatic tumour cells stimulate the proliferation of PaSCs through the secretion of PDGF, and induce PaSC production of ECM proteins by secreting TGF-
Pancreatic cancer cells also stimulate proliferation, ECM production and TIMP1 production in PaSCs.[5] The production of these factors is regulated by fibroblast growth factor 2, TGF-
A hypoxic environment in tumours influences pancreatic cancer progression.[12] An oxygen deficient environment concomitantly exists not only in cancer cells but also in surrounding pancreatic stellate cells.[12] The cellular response to hypoxia is mediated by the transcription factor HIF-1, which is a heterodimer protein composed of
Ongoing research
[edit]Treatment of chronic pancreatitis and pancreatic cancer aims to target the major mechanisms involved in both their activation and proliferation.[1] For example, inhibition of the receptors PDGF, TGF-
Anti-fibrosis treatment strategies targeting PaSCs include inhibition of the activation of quiescent PaSCs.[5] Agents such as angiotensin receptor blockers, serine protease inhibitors and adenine dinucleotide phosphate oxidase inhibit the activation and function of PaSCs.[5] Camostat mesilate, an oral protease inhibitor, that is used to treat patients with chronic pancreatitis inhibited the proliferation and MCP-1 production in PaSCs in vitro.[5] The success and effect of anti-fibrosis therapies in pancreatic cancer treatment, however, remains unclear.[5]
Rat PaSCs express COX-2 when stimulated with TGF beta 1 (TGF-
History
[edit]While the discovery of hepatic stellate cells is attributed to Karl Wilhelm von Kupffer in 1876, who had termed them “stellate cells”, the original discovery is attributed to more than one research group.[4] The first documented observations of PaSCs were recorded by Watari et al. in 1982.[13] Watari observed the pancreas of vitamin A primed mice using fluorescence microscopy and electron microscopy.[9] Cells displaying fading blue-green fluorescence typical of vitamin A in the periacinar region of pancreas was observed.[9] Watari likened these cells to hepatic stellate cells.[9] The publication of two seminal research papers in 1998 outlining the isolation of these cells provided an in vitro method by which researchers may characterise PaSCs in both health and pathology.[3]
See also
[edit]References
[edit]- ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at Omary MB, Lugea A, Lowe AW, Pandol SJ (January 2007). "The pancreatic stellate cell: a star on the rise in pancreatic diseases". J. Clin. Invest. 117 (1): 50–9. doi:10.1172/JCI30082. ISSN 0021-9738. PMC 1716214. PMID 17200706.
- ^ a b Charo C, Holla V, Arumugam T, Hwang R, Yang P, Dubois RN, Menter DG, Logsdon CD, Ramachandran V (April 2013). "Prostaglandin E2 regulates pancreatic stellate cell activity via the EP4 receptor". Pancreas. 42 (3): 467–74. doi:10.1097/MPA.0b013e318264d0f8. ISSN 0885-3177. PMC 3600062. PMID 23090667.
- ^ a b Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA, Pirola RC, Wilson JS (July 1998). "Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture". Gut. 43 (1): 128–33. doi:10.1136/gut.43.1.128. ISSN 0017-5749. PMC 1727174. PMID 9771417.
- ^ a b c Ferdek PE, Jakubowska MA (September 2017). "Biology of pancreatic stellate cells-more than just pancreatic cancer". Pflügers Arch. 469 (9): 1039–1050. doi:10.1007/s00424-017-1968-0. ISSN 0031-6768. PMC 5554282. PMID 28382480.
- ^ a b c d e f g h i j k l m n o p Masamune A, Watanabe T, Kikuta K, Shimosegawa T (November 2009). "Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis". Clin. Gastroenterol. Hepatol. 7 (11 Suppl): S48–54. doi:10.1016/j.cgh.2009.07.038. ISSN 1542-3565. PMID 19896099.
- ^ a b c d Masamune A, Shimosegawa T (2009). "Signal transduction in pancreatic stellate cells". J. Gastroenterol. 44 (4): 249–60. doi:10.1007/s00535-009-0013-2. ISSN 0944-1174. PMID 19271115.
- ^ a b c d e f g h Apte MV, Phillips PA, Fahmy RG, Darby SJ, Rodgers SC, McCaughan GW, Korsten MA, Pirola RC, Naidoo D, Wilson JS (April 2000). "Does alcohol directly stimulate pancreatic fibrogenesis? Studies with rat pancreatic stellate cells". Gastroenterology. 118 (4): 780–94. doi:10.1016/S0016-5085(00)70148-X. ISSN 0016-5085. PMID 10734030.
- ^ Shinozaki S, Ohnishi H, Hama K, Kita H, Yamamoto H, Osawa H, Sato K, Tamada K, Mashima H, Sugano K (July 2008). "Indian hedgehog promotes the migration of rat activated pancreatic stellate cells by increasing membrane type-1 matrix metalloproteinase on the plasma membrane". J. Cell. Physiol. 216 (1): 38–46. doi:10.1002/jcp.21372. ISSN 0021-9541. PMID 18286538. S2CID 11204851.
- ^ a b c d e Apte MV, Pirola RC, Wilson JS (2012). "Pancreatic stellate cells: a starring role in normal and diseased pancreas". Front Physiol. 3: 344. doi:10.3389/fphys.2012.00344. ISSN 1664-042X. PMC 3428781. PMID 22973234.
- ^ Hennigs JK, Seiz O, Spiro J, Berna MJ, Baumann HJ, Klose H, Pace A (July 2011). "Molecular basis of P2-receptor-mediated calcium signaling in activated pancreatic stellate cells". Pancreas. 40 (5): 740–6. doi:10.1097/MPA.0b013e31821b5b68. ISSN 0885-3177. PMID 21654543. S2CID 21538837.
- ^ a b Mews P, Phillips P, Fahmy R, Korsten M, Pirola R, Wilson J, Apte M (April 2002). "Pancreatic stellate cells respond to inflammatory cytokines: potential role in chronic pancreatitis". Gut. 50 (4): 535–41. doi:10.1136/gut.50.4.535. ISSN 0017-5749. PMC 1773172. PMID 11889076.
- ^ a b c d e f Xu Z, Vonlaufen A, Phillips PA, Fiala-Beer E, Zhang X, Yang L, Biankin AV, Goldstein D, Pirola RC, Wilson JS, Apte MV (November 2010). "Role of pancreatic stellate cells in pancreatic cancer metastasis". Am. J. Pathol. 177 (5): 2585–96. doi:10.2353/ajpath.2010.090899. ISSN 0002-9440. PMC 2966814. PMID 20934972.
- ^ Watari N, Hotta Y, Mabuchi Y (March 1982). "Morphological studies on a vitamin A-storing cell and its complex with macrophage observed in mouse pancreatic tissues following excess vitamin A administration". Okajimas Folia Anat Jpn. 58 (4–6): 837–58. doi:10.2535/ofaj1936.58.4-6_837. ISSN 0030-154X. PMID 7122019.
External links
[edit]- Media related to Pancreatic stellate cell at Wikimedia Commons