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• W2084920452 abstract "See “Extensive pancreas regeneration following acinar-specific disruption of Xbp1 in mice,” by Hess DA, Humphrey SE, Ishibashi J, et al, on page 1463. See “Extensive pancreas regeneration following acinar-specific disruption of Xbp1 in mice,” by Hess DA, Humphrey SE, Ishibashi J, et al, on page 1463. The adult pancreas is composed of several highly specialized cell types that correspond with the different functions of this organ. The endocrine pancreas is composed of clusters of endocrine cells that form the islets of Langerhans, and secrete hormones, most notably insulin and glucagon. The exocrine pancreas is formed by acini, centroacinar cells and the ductal system, and its function is to produce digestive enzymes and secrete them into the digestive tract (for review, see Williams1Williams J.A. Regulation of acinar cell function in the pancreas.Curr Opin Gastroenterol. 2010; 26: 478-483Google Scholar). The unfolded protein response (UPR) protects cells from endoplasmic reticulum (ER) stress caused by accumulation of misfolded proteins2Gregersen N. Bross P. Protein misfolding and cellular stress: an overview.Meth Mol Biol. 2010; 648: 3-23Google Scholar and plays a role in several human diseases, including inflammatory bowel disease.3Kaser A. Blumberg R.S. Autophagy, microbial sensing, endoplasmic reticulum stress, and epithelial function in inflammatory bowel disease.Gastroenterology. 2011; 140: 1738-1747Google Scholar Three different pathways mediating the UPR have been described: IRE1/XBP1, ATF6, and PERK.4Ron D. Walter P. Signal integration in the endoplasmic reticulum unfolded protein response.Nat Rev Mol Cell Biol. 2007; 8: 519-529Google Scholar Because pancreatic acinar cells need to produce and process massive amounts of proteins, they are particularly susceptible to ER stress.5Kowalik A.S. Johnson C.L. Chadi S.A. et al.Mice lacking the transcription factor Mist1 exhibit an altered stress response and increased sensitivity to caerulein-induced pancreatitis.Am J Physiol Gastrointest Liver Physiol. 2007; 292: G1123-G1132Google Scholar, 6Kubisch C.H. Logsdon C.D. Secretagogues differentially activate endoplasmic reticulum stress responses in pancreatic acinar cells.Am J Physiol Gastrointest Liver Physiol. 2007; 292: G1804-G1812Google Scholar, 7Kubisch C.H. Sans M.D. Arumugam T. et al.Early activation of endoplasmic reticulum stress is associated with arginine-induced acute pancreatitis.Am J Physiol Gastrointest Liver Physiol. 2006; 291: G238-G245Google Scholar Indeed, the IRE1/XBP1 pathway is active in the exocrine pancreas,7Kubisch C.H. Sans M.D. Arumugam T. et al.Early activation of endoplasmic reticulum stress is associated with arginine-induced acute pancreatitis.Am J Physiol Gastrointest Liver Physiol. 2006; 291: G238-G245Google Scholar, 8Romero-Ramirez L. Cao H. Regalado M.P. et al.X box-binding protein 1 regulates angiogenesis in human pancreatic adenocarcinomas.Transl Oncol. 2009; 2: 31-38Scopus (75) Google Scholar and its activity is increased during acute pancreatitis.5Kowalik A.S. Johnson C.L. Chadi S.A. et al.Mice lacking the transcription factor Mist1 exhibit an altered stress response and increased sensitivity to caerulein-induced pancreatitis.Am J Physiol Gastrointest Liver Physiol. 2007; 292: G1123-G1132Google Scholar, 6Kubisch C.H. Logsdon C.D. Secretagogues differentially activate endoplasmic reticulum stress responses in pancreatic acinar cells.Am J Physiol Gastrointest Liver Physiol. 2007; 292: G1804-G1812Google Scholar, 7Kubisch C.H. Sans M.D. Arumugam T. et al.Early activation of endoplasmic reticulum stress is associated with arginine-induced acute pancreatitis.Am J Physiol Gastrointest Liver Physiol. 2006; 291: G238-G245Google Scholar, 9Lugea A. Tischler D. Nguyen J. et al.Adaptive unfolded protein response attenuates alcohol-induced pancreatic damage.Gastroenterology. 2011; 140: 987-997Google Scholar Embryonic deletion of Xbp1 results in severe loss of acinar cells and neonatal mortality indicating an essential role for this pathway for acinar cell development.10Huh W.J. Esen E. Geahlen J.H. et al.XBP1 controls maturation of gastric zymogenic cells by induction of MIST1 and expansion of the rough endoplasmic reticulum.Gastroenterology. 2010; 139: 2038-2049Google Scholar Given the importance of the Xbp1 pathway in the maintenance of acinar cells, it is hardly surprising that an intact Xbp1 pathway plays an essential role in protecting the pancreas from damage. In a recent study published in Gastroenterology,9Lugea A. Tischler D. Nguyen J. et al.Adaptive unfolded protein response attenuates alcohol-induced pancreatic damage.Gastroenterology. 2011; 140: 987-997Google Scholar mice heterozygous for Xbp1, that have a normal pancreas as adults, were shown to be highly susceptible to alcoholic pancreatitis, and sustain more severe damage than their wild-type counterpart, with increase of ER stress and apoptosis of acinar cells that are replaced by tubular complexes. The study by Konieczny et al in this issue examines for the first time the role of Xbp1 in adult pancreatic acinar cells.11Hess D.A. Humphrey S.E. Ishibashi J. et al.Extensive pancreas regeneration following acinar-specific disruption of Xbp1 in mice.Gastroenterology. 2011; 141: 1463-1472Google Scholar To investigate the role of Xbp1 in the maintenance of the pancreatic acinar cells, the authors have generated a conditional, acinar-specific knockout of Xbp1, using Mist1-CreER12Habbe N. Shi G. Meguid R.A. et al.Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice.Proc Natl Acad Sci U S A. 2008; 105: 18913-18918Google Scholar, 13Shi G. Zhu L. Sun Y. et al.Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia.Gastroenterology. 2009; 136: 1368-1378Google Scholar and a conditional, floxed allele of Xbp114Lee A.H. Scapa E.F. Cohen D.E. et al.Regulation of hepatic lipogenesis by the transcription factor XBP1.Science. 2008; 320: 1492-1496Google Scholar that behaves like the wild-type gene in absence of recombination, but can be inactivated by active Cre. Mist1 is an acinar-cell–specific transcription factor that plays an important role in maintaining the acinar cell identity and regulating acinar proliferation15Lemercier C. To R.Q. Swanson B.J. et al.Mist1: a novel basic helix-loop-helix transcription factor exhibits a developmentally regulated expression pattern.Dev Biol. 1997; 182: 101-113Google Scholar, 16Zhu L. Tran T. Rukstalis J.M. et al.Inhibition of Mist1 homodimer formation induces pancreatic acinar-to-ductal metaplasia.Mol Cell Biol. 2004; 24: 2673-2681Google Scholar, 17Jia D. Sun Y. Konieczny S.F. Mist1 regulates pancreatic acinar cell proliferation through p21 CIP1/WAF1.Gastroenterology. 2008; 135: 1687-1697Abstract Full Text Full Text PDF Scopus (43) Google Scholar; Mist1-CreER mice express an estrogen-receptor fusion version of the Cre recombinase that can be activated by administering tamoxifen to the mice. Once activated in adult mice, Mist1-CreER driver recombination exclusively in acinar cells within the exocrine pancreas, with rare targeting of islet cells. In addition to the pancreatic acinar cells, Mist1-Cre is expressed in other acinar cells including salivary glands and zymogenic chief cells of the gastric mucosa.15Lemercier C. To R.Q. Swanson B.J. et al.Mist1: a novel basic helix-loop-helix transcription factor exhibits a developmentally regulated expression pattern.Dev Biol. 1997; 182: 101-113Google Scholar However, none of these cells are essential for life or impact pancreatic function. Importantly, lineage tracing studies using a reporter mouse strain revealed that about 90% of the acinar cells undergo recombination, but the remaining 10% do not owing to mosaicism in the Cre expression or activity (Figure 1A, B). The use of Mist1-CreER, and the availability of a conditional Xbp1 allele,14Lee A.H. Scapa E.F. Cohen D.E. et al.Regulation of hepatic lipogenesis by the transcription factor XBP1.Science. 2008; 320: 1492-1496Google Scholar has allowed the authors to inactivate Xbp1 in the adult pancreas, thus bypassing the early lethality effect. Upon deletion of Xbp1, acinar cells underwent profound alterations, with extensive disruption of the exocrine pancreas observed 4 weeks after tamoxifen treatment. In particular, the acinar cells showed loss of secretory granules, disorganized ER, and vastly reduced cytoplasm (Figure 1C), in addition to loss of expression of differentiation markers such as Mist1. In contrast, the acinar cells that had not recombined the Xbp1 locus did not show any sign of cellular damage. The presence of severe ER stress in acinar cells, upon Xbp1 deletion, indicates an absolute requirement for the XBP1/IRE pathway in this cell type that cannot be compensated for by the ATF6 and PERK pathways, still functional in those cells. This interesting finding indicates a different requirement for individual UPR pathways in different secretory cells types; for instance, the zymogenic cells in the stomach survive Xbp1 deletion and continue expressing zymogenic markers.10Huh W.J. Esen E. Geahlen J.H. et al.XBP1 controls maturation of gastric zymogenic cells by induction of MIST1 and expansion of the rough endoplasmic reticulum.Gastroenterology. 2010; 139: 2038-2049Google Scholar The nonzymogenic acinar cells were unable to recover from ER stress, and underwent apoptosis, so that all of the Xbp1-null cells are eventually lost from the pancreas and about 90% of the exocrine pancreas was lost within 4 weeks post-tamoxifen. At the same time, both the Xbp-positive cells and the centroacinar cells re-enter the cell cycle and start dividing actively. In addition, both expression of the acinar marker Mist1 and expression of pancreatic progenitor markers such as Nestin, Hes1, and Sox9 were transiently induced, to slowly return to normal levels by 6 weeks post-tamoxifen. The expression of Hes1 and Sox9 was restricted to centroacinar-terminal ductal cells, and was not observed in the zymogenic acinar cells, whereas Mist1 expression was confined to the acinar cells. Strikingly, within 6–8 weeks post-tamoxifen the pancreata showed an almost complete recovery, with the pancreas composed of zymogen-filled, normal appearing acini (Figure 1D). Some limited areas with persistent inflammatory infiltrates, and some Sox9-positive tubular complexes persisted, and an increase in the intrapancreatic adipose tissue was also observed, but most of the pancreas had recovered its normal cellular composition and architecture. The acini in the recovered pancreas, however, were significantly larger, an average of 2-fold, than those of age matched littermates. This is interesting, because it might reflect the need for compensatory hypertrophy once the proliferation potential of the acinar cells has been exhausted. A limited proliferation potential has been observed in the pancreatic progenitor population, when ablation of a subset of these cells does not elicit compensatory proliferation and results in small organ size up to the adult stage, in striking contrast with the liver, which can quickly and completely return to normal size under the same conditions.18Stanger B.Z. Tanaka A.J. Melton D.A. Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver.Nature. 2007; 445: 886-891Google Scholar Given the striking recovery of acinar cells, the question arises whether they derive from a progenitor cell population within the pancreas, or from the acinar cells that were spared from the Xbp1 loss and induction of apoptosis. The authors lean toward a model of acinar cells deriving exclusively from the residual acinar cells, although they hypothesize that the actively proliferating centroacinar cells might be forming the tubular complexes that are left in the regenerated pancreas. However, lineage-tracing experiments are needed to conclusively ascertain the origin of the different cell populations following pancreatic repair. In a different model of acinar cell loss, cerulein-induced acute pancreatitis, a more modest acinar cell loss (estimated at 10% of the total) is rapidly followed by regeneration and complete repair,19Strobel O. Dor Y. Stirman A. et al.Beta cell transdifferentiation does not contribute to preneoplastic/metaplastic ductal lesions of the pancreas by genetic lineage tracing in vivo.Proc Natl Acad Sci U S A. 2007; 104: 4419-4424Google Scholar and accompanied by reactivation of embryonic signaling pathways.20Jensen J.N. Cameron E. Garay M.V. et al.Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration.Gastroenterology. 2005; 128: 728-741Google Scholar, 21Fendrich V. Esni F. Garay M.V. et al.Hedgehog signaling is required for effective regeneration of exocrine pancreas.Gastroenterology. 2008; 135: 621-631Abstract Full Text Full Text PDF Scopus (156) Google Scholar, 22Siveke J.T. Lubeseder-Martellato C. Lee M. et al.Notch signaling is required for exocrine regeneration after acute pancreatitis.Gastroenterology. 2008; 134: 544-555Abstract Full Text Full Text PDF Scopus (130) Google Scholar Cerulein is a cholecystokinin agonist widely used for its ability to simulate pancreatitis in mice. Administration of cerulein for a limited time frame results in acute pancreatitis characterized by loss of acinar cells, infiltration of inflammatory cells, and edema. Lineage tracing of the acinar cells in this model have determined that the newly formed acinar cells exclusively derive from preexisting acinar cells, with no contribution from other compartments within the pancreas.23Strobel O. Dor Y. Alsina J. et al.In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia.Gastroenterology. 2007; 133: 1999-2009Abstract Full Text Full Text PDF Scopus (202) Google Scholar Therefore, whether a progenitor-like cell able to give rise to exocrine cells in the pancreas is still a matter of debate. However, an indication of the plasticity of the pancreatic lineages comes from mouse models of pancreatic cancer. Pancreatic cancer is almost invariably linked with a mutation in the Kras oncogene; expression of this oncogenic form of Kras in the pancreas reproduces the progression of the human disease.24Hingorani S.R. Petricoin E.F. Maitra A. et al.Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse.Cancer Cell. 2003; 4: 437-450Google Scholar, 25Aguirre A.J. Bardeesy N. Sinha M. et al.Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma.Genes Dev. 2003; 17: 3112-3126Google Scholar Interestingly, several pancreatic lineages have been shown to be able to contribute to carcinogenesis26Gidekel Friedlander S.Y. Chu G.C. Snyder E.L. et al.Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras.Cancer Cell. 2009; 16: 379-389Google Scholar and dedifferentiation of acinar cells to duct-like cells expressing progenitor markers might be a first step in the carcinogenesis process.12Habbe N. Shi G. Meguid R.A. et al.Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice.Proc Natl Acad Sci U S A. 2008; 105: 18913-18918Google Scholar, 13Shi G. Zhu L. Sun Y. et al.Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia.Gastroenterology. 2009; 136: 1368-1378Google Scholar, 27Morris J.Pt. Cano D.A. Sekine S. et al.Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice.J Clin Invest. 2010; 120: 508-520Google Scholar In summary, this study11Hess D.A. Humphrey S.E. Ishibashi J. et al.Extensive pancreas regeneration following acinar-specific disruption of Xbp1 in mice.Gastroenterology. 2011; 141: 1463-1472Google Scholar greatly increases our understanding of 2 important processes in pancreatic biology. First, it sheds light on the mechanisms acinar cells use to cope with their elevated protein synthesis and protect themselves from ER stress. Second, it contributes a model of pancreatic damage and repair that will complement existing systems. Both of these aspects have important implications for pancreatic diseases, including pancreatitis and pancreatic cancer. Extensive Pancreas Regeneration Following Acinar-Specific Disruption of Xbp1 in MiceGastroenterologyVol. 141Issue 4PreviewProgression of diseases of the exocrine pancreas, which include pancreatitis and cancer, is associated with increased levels of cell stress. Pancreatic acinar cells are involved in development of these diseases and, because of their high level of protein output, they require an efficient, unfolded protein response (UPR) that mediates recovery from endoplasmic reticulum (ER) stress following the accumulation of misfolded proteins. Full-Text PDF" @default.
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• W2084920452 title "Pancreatic Stress and Regeneration" @default.
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