CoChat
Sign Up
Cited by 197Pancreatitis Pathology and TreatmentPancreatic and Hepatic Oncology ResearchPancreatic function and diabetes

Regeneration and Repair of the Exocrine Pancreas

Open access
Murtaugh, L. Charles, Keefe, Matthew D.·2015·Annual Review of Physiology
DOI 10.1146/annurev-physiol-021014-071727PMC PMC4324082
Open this paper in CoChat — free accountOpen PDF

Abstract

Pancreatitis is caused by inflammatory injury to the exocrine pancreas, from which both humans and animal models appear to recover via regeneration of digestive enzyme–producing acinar cells. This regenerative process involves transient phases of inflammation, metaplasia, and redifferentiation, driven by cell-cell interactions between acinar cells, leukocytes, and resident fibroblasts. The NFκB signaling pathway is a critical determinant of pancreatic inflammation and metaplasia, whereas a number of developmental signals and transcription factors are devoted to promoting acinar redifferentiation after injury. Imbalances between these proinflammatory and prodifferentiation pathways contribute to chronic pancreatitis, characterized by persistent inflammation, fibrosis, and acinar dedifferentiation. Loss of acinar cell differentiation also drives pancreatic cancer initiation, providing a mechanistic link between pancreatitis and cancer risk. Unraveling the molecular bases of exocrine regeneration may identify new therapeutic targets for treatment and prevention of both of these deadly diseases.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1146/annurev-physiol-021014-071727

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Augmented Hedgehog, Notch, and Wnt/b-catenin signaling are mandatory for regeneration in mice after experimental induction of pancreatitis.

    “Among others, augmented Hedgehog, Notch, and Wnt/b-catenin signaling were delineated as mandatory for regeneration in mice after experimental induction of pancreatitis [21–24].”

    From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [21]

    In “Developmental signals regulating pancreatic regeneration” (page not provided), the review reports that Hedgehog signaling is required for acinar re-differentiation after caerulein-induced pancreatitis and that Notch promotes it, although the Notch requirement may be indirect. It also reports that β-catenin is important for proliferative expansion of surviving acini, but not for their re-differentiation; whether that effect depends on Wnt ligands is unknown. Thus, calling augmented signaling through all three pathways mandatory for regeneration overstates the source. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Common mechanisms and similar genetic programs between stem cell induction, organ homeostasis, and regeneration from injury have been identified for the pancreas.

    “Common mechanisms and similar genetic programs between stem cell induction, organ homeostasis, and regeneration from injury have been identified for the pancreas [20, 21].”

    From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [21]

    The sections on developmental signals and transcription factors report that regulators involved in pancreatic development or homeostasis also have roles in regeneration after injury (page unavailable in our copy). They do not establish the claimed overlap with stem cell induction, so the three-way comparison is only partly supported. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 120 · Cited by 197

Research works printed but not linked: 113

  1. [1]Steinberg WM 2006 Acute Pancreatitis Sleisenger & Fordtran’s gastrointestinal and liver disease: pathophysiology, diagnosis, management Sleisenger MH Feldman M Friedman LS Brandt LJ Philadelphia Saunders
  2. [2]Pan FC Wright C 2011 Pancreas organogenesis: From bud to plexus to gland Dev Dyn 240 530 65 21337462
  3. [3]Shih HP Wang A Sander M 2013 Pancreas organogenesis: from lineage determination to morphogenesis Annu Rev Cell Dev Biol 29 81 105 23909279
  4. [4]Kretzschmar K Watt FM 2012 Lineage tracing Cell 148 33 45 22265400
  5. [5]Pan FC Bankaitis ED Boyer D Xu X Van de Casteele M Magnuson MA Heimberg H Wright CV 2013 Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration Development 140 751 64 23325761 PMC3557774
  6. [6]Masui T Long Q Beres TM Magnuson MA MacDonald RJ 2007 Early pancreatic development requires the vertebrate Suppressor of Hairless (RBPJ) in the PTF1 bHLH complex Genes Dev 21 2629 43 17938243 PMC2000326
  7. [7]Kopp JL Dubois CL Schaffer AE Hao E Shih HP Seymour PA Ma J Sander M 2011 Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas Development 138 653 65 21266405 PMC3026412
  8. [8]Solar M Cardalda C Houbracken I Martin M Maestro MA De Medts N Xu X Grau V Heimberg H Bouwens L Ferrer J 2009 Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth Dev Cell 17 849 60 20059954
  9. [9]Zhou Q Law AC Rajagopal J Anderson WJ Gray PA Melton DA 2007 A multipotent progenitor domain guides pancreatic organogenesis Dev Cell 13 103 14 17609113
  10. [10]Kopinke D Murtaugh LC 2010 Exocrine-to-endocrine differentiation is detectable only prior to birth in the uninjured mouse pancreas BMC Dev Biol 10 38 20377894 PMC2858732
  11. [11]Forsmark CE 2006 Chronic Pancreatitis Sleisenger & Fordtran’s gastrointestinal and liver disease: pathophysiology, diagnosis, management Sleisenger MH Feldman M Friedman LS Brandt LJ Philadelphia Saunders
  12. [12]Greer JB Whitcomb DC 2009 Inflammation and pancreatic cancer: an evidence-based review Curr Opin Pharmacol 9 411 8 19589727
  13. [13]Whitcomb DC 2013 Genetic risk factors for pancreatic disorders Gastroenterology 144 1292 302 23622139 PMC3684061
  14. [14]Dawra R Sah RP Dudeja V Rishi L Talukdar R Garg P Saluja AK 2011 Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis Gastroenterology 141 2210 7 e2 21875495 PMC3587766
  15. [15]Singh VP Chari ST 2005 Protease inhibitors in acute pancreatitis: lessons from the bench and failed clinical trials Gastroenterology 128 2172 4 15940654
  16. [16]Logsdon CD Ji B 2013 The role of protein synthesis and digestive enzymes in acinar cell injury Nat Rev Gastroenterol Hepatol 10 362 70 23507798 PMC3902846
  17. [17]Bockman DE 1997 Morphology of the exocrine pancreas related to pancreatitis Microsc Res Tech 37 509 19 9220428
  18. [18]Bockman DE Boydston WR Anderson MC 1982 Origin of tubular complexes in human chronic pancreatitis Am J Surg 144 243 9 7102934
  19. [19]Willemer S Adler G 1989 Histochemical and ultrastructural characteristics of tubular complexes in human acute pancreatitis Dig Dis Sci 34 46 55 2535980
  20. [20]Ebert M Yokoyama M Ishiwata T Friess H Buchler MW Malfertheiner P Korc M 1999 Alteration of fibroblast growth factor and receptor expression after acute pancreatitis in humans Pancreas 18 240 6 10206481
  21. [21]Zimmermann A Gloor B Kappeler A Uhl W Friess H Buchler MW 2002 Pancreatic stellate cells contribute to regeneration early after acute necrotising pancreatitis in humans Gut 51 574 8 12235083 PMC1773379
  22. [22]Lerch MM Gorelick FS 2013 Models of acute and chronic pancreatitis Gastroenterology 144 1180 93 23622127
  23. [23]Willemer S Elsasser HP Adler G 1992 Hormone-induced pancreatitis Eur Surg Res 24 Suppl 1 29 39 1601022
  24. [24]Halangk W Lerch MM Brandt-Nedelev B Roth W Ruthenbuerger M Reinheckel T Domschke W Lippert H Peters C Deussing J 2000 Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis J Clin Invest 106 773 81 10995788 PMC381392
  25. [25]Hofbauer B Saluja AK Lerch MM Bhagat L Bhatia M Lee HS Frossard JL Adler G Steer ML 1998 Intra-acinar cell activation of trypsinogen during caerulein-induced pancreatitis in rats Am J Physiol 275 G352 62 9688663
  26. [26]Sah RP Dawra RK Saluja AK 2013 New insights into the pathogenesis of pancreatitis Curr Opin Gastroenterol 29 523 30 23892538 PMC3934497
  27. [27]Jensen JN Cameron E Garay MV Starkey TW Gianani R Jensen J 2005 Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration Gastroenterology 128 728 41 15765408
  28. [28]Morris JPt Cano DA Sekine S Wang SC Hebrok M 2010 Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice J Clin Invest 120 508 20 20071774 PMC2810083
  29. [29]Zhong B Zhou Q Toivola DM Tao GZ Resurreccion EZ Omary MB 2004 Organ-specific stress induces mouse pancreatic keratin overexpression in association with NF-kappaB activation J Cell Sci 117 1709 19 15075232
  30. [30]De La OJP Murtaugh LC 2009 Notch and Kras in pancreatic cancer: at the crossroads of mutation, differentiation and signaling Cell Cycle 8 1860 4 19440048 PMC2719432
  31. [31]Fendrich V Esni F Garay MV Feldmann G Habbe N Jensen JN Dor Y Stoffers D Jensen J Leach SD Maitra A 2008 Hedgehog signaling is required for effective regeneration of exocrine pancreas Gastroenterology 135 621 31 18515092 PMC2666349
  32. [32]Neuschwander-Tetri BA Bridle KR Wells LD Marcu M Ramm GA 2000 Repetitive acute pancreatic injury in the mouse induces procollagen alpha1(I) expression colocalized to pancreatic stellate cells Lab Invest 80 143 50 10701684
  33. [33]Walker NI 1987 Ultrastructure of the rat pancreas after experimental duct ligation. I. The role of apoptosis and intraepithelial macrophages in acinar cell deletion Am J Pathol 126 439 51 3826300 PMC1899643
  34. [35]Lehv M Fitzgerald PJ 1968 Pancreatic acinar cell regeneration. IV. Regeneration after resection Am J Pathol 53 513 35 5677136 PMC2013418
  35. [36]Bonner-Weir S Trent DF Weir GC 1983 Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release J Clin Invest 71 1544 53 6134752 PMC370360
  36. [37]Watanabe H Saito H Rychahou PG Uchida T Evers BM 2005 Aging is associated with decreased pancreatic acinar cell regeneration and phosphatidylinositol 3-kinase/Akt activation Gastroenterology 128 1391 404 15887120
  37. [38]Rankin MM Kushner JA 2009 Adaptive beta-cell proliferation is severely restricted with advanced age Diabetes 58 1365 72 19265026 PMC2682671
  38. [39]Berrocal T Luque AA Pinilla I Lassaletta L 2005 Pancreatic regeneration after near-total pancreatectomy in children with nesidioblastosis Pediatr Radiol 35 1066 70 16003534
  39. [41]Tsiotos GG Barry MK Johnson CD Sarr MG 1999 Pancreas regeneration after resection: does it occur in humans? Pancreas 19 310 3 10505763
  40. [42]Dor Y Brown J Martinez OI Melton DA 2004 Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation Nature 429 41 6 15129273
  41. [43]Nir T Melton DA Dor Y 2007 Recovery from diabetes in mice by beta cell regeneration J Clin Invest 117 2553 61 17786244 PMC1957545
  42. [44]Strobel O Dor Y Alsina J Stirman A Lauwers G Trainor A Castillo CF Warshaw AL Thayer SP 2007 In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia Gastroenterology 133 1999 2009 18054571 PMC2254582
  43. [48]Criscimanna A Speicher JA Houshmand G Shiota C Prasadan K Ji B Logsdon CD Gittes GK Esni F 2011 Duct cells contribute to regeneration of endocrine and acinar cells following pancreatic damage in adult mice Gastroenterology 141 1451 62 62 e1 6 21763240 PMC4326039
  44. [49]Frossard JL Rubbia-Brandt L Wallig MA Benathan M Ott T Morel P Hadengue A Suter S Willecke K Chanson M 2003 Severe acute pancreatitis and reduced acinar cell apoptosis in the exocrine pancreas of mice deficient for the Cx32 gene Gastroenterology 124 481 93 12557153
  45. [50]Dimagno MJ Lee SH Hao Y Zhou SY McKenna BJ Owyang C 2005 A proinflammatory, antiapoptotic phenotype underlies the susceptibility to acute pancreatitis in cystic fibrosis transmembrane regulator (−/−) mice Gastroenterology 129 665 81 16083720
  46. [51]Cano DA Sekine S Hebrok M 2006 Primary cilia deletion in pancreatic epithelial cells results in cyst formation and pancreatitis Gastroenterology 131 1856 69 17123526
  47. [52]Crawford HC Scoggins CR Washington MK Matrisian LM Leach SD 2002 Matrix metalloproteinase-7 is expressed by pancreatic cancer precursors and regulates acinar-to-ductal metaplasia in exocrine pancreas J Clin Invest 109 1437 44 12045257 PMC150998
  48. [53]Magnuson MA Osipovich AB 2013 Pancreas-specific Cre driver lines and considerations for their prudent use Cell Metab 18 9 20 23823474 PMC3732107
  49. [54]Kopinke D Brailsford M Pan FC Magnuson MA Wright CV Murtaugh LC 2012 Ongoing Notch signaling maintains phenotypic fidelity in the adult exocrine pancreas Dev Biol 362 57 64 22146645 PMC3254730
  50. [55]Stanger BZ Stiles B Lauwers GY Bardeesy N Mendoza M Wang Y Greenwood A Cheng KH McLaughlin M Brown D Depinho RA Wu H Melton DA Dor Y 2005 Pten constrains centroacinar cell expansion and malignant transformation in the pancreas Cancer Cell 8 185 95 16169464
  51. [56]Guerra C Schuhmacher AJ Canamero M Grippo PJ Verdaguer L Perez-Gallego L Dubus P Sandgren EP Barbacid M 2007 Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice Cancer Cell 11 291 302 17349585
  52. [57]Gukovsky I Gukovskaya AS Blinman TA Zaninovic V Pandol SJ 1998 Early NF-kappaB activation is associated with hormone-induced pancreatitis Am J Physiol 275 G1402 14 9843778
  53. [58]Grady T Liang P Ernst SA Logsdon CD 1997 Chemokine gene expression in rat pancreatic acinar cells is an early event associated with acute pancreatitis Gastroenterology 113 1966 75 9394737
  54. [59]Gukovskaya AS Gukovsky I Zaninovic V Song M Sandoval D Gukovsky S Pandol SJ 1997 Pancreatic acinar cells produce, release, and respond to tumor necrosis factor-alpha. Role in regulating cell death and pancreatitis J Clin Invest 100 1853 62 9312187 PMC508372
  55. [60]Omary MB Lugea A Lowe AW Pandol SJ 2007 The pancreatic stellate cell: a star on the rise in pancreatic diseases J Clin Invest 117 50 9 17200706 PMC1716214
  56. [61]Apte MV Haber PS Applegate TL Norton ID McCaughan GW Korsten MA Pirola RC Wilson JS 1998 Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture Gut 43 128 33 9771417 PMC1727174
  57. [62]Landsman L Nijagal A Whitchurch TJ Vanderlaan RL Zimmer WE Mackenzie TC Hebrok M 2011 Pancreatic mesenchyme regulates epithelial organogenesis throughout development PLoS Biol 9 e1001143 21909240 PMC3167782
  58. [63]Troeger JS Mederacke I Gwak GY Dapito DH Mu X Hsu CC Pradere JP Friedman RA Schwabe RF 2012 Deactivation of hepatic stellate cells during liver fibrosis resolution in mice Gastroenterology 143 1073 83 e22 22750464 PMC3848328
  59. [64]Ozdemir BC Pentcheva-Hoang T Carstens JL Zheng X Wu CC Simpson TR Laklai H Sugimoto H Kahlert C Novitskiy SV De Jesus-Acosta A Sharma P Heidari P Mahmood U Chin L Moses HL Weaver VM Maitra A Allison JP LeBleu VS Kalluri R 2014 Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival Cancer Cell 25 719 34 24856586 PMC4180632
  60. [65]Rhim AD Oberstein PE Thomas DH Mirek ET Palermo CF Sastra SA Dekleva EN Saunders T Becerra CP Tattersall IW Westphalen CB Kitajewski J Fernandez-Barrena MG Fernandez-Zapico ME Iacobuzio-Donahue C Olive KP Stanger BZ 2014 Stromal Elements Act to Restrain, Rather Than Support, Pancreatic Ductal Adenocarcinoma Cancer Cell PMC4096698 24856585
  61. [66]Gukovsky I Li N Todoric J Gukovskaya A Karin M 2013 Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer Gastroenterology 144 1199 209 e4 23622129 PMC3786712
  62. [67]Zheng L Xue J Jaffee EM Habtezion A 2013 Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma Gastroenterology 144 1230 40 23622132 PMC3641650
  63. [68]Sendler M Dummer A Weiss FU Kruger B Wartmann T Scharffetter-Kochanek K van Rooijen N Malla SR Aghdassi A Halangk W Lerch MM Mayerle J 2013 Tumour necrosis factor alpha secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice Gut 62 430 9 22490516
  64. [69]Treiber M Neuhofer P Anetsberger E Einwachter H Lesina M Rickmann M Liang S Kehl T Nakhai H Schmid RM Algul H 2011 Myeloid, but not pancreatic, RelA/p65 is required for fibrosis in a mouse model of chronic pancreatitis Gastroenterology 141 1473 85 85 e1 7 21763242
  65. [70]Folias AE Penaranda C Su AL Bluestone JA Hebrok M 2014 Aberrant Innate Immune Activation following Tissue Injury Impairs Pancreatic Regeneration PLoS One 9 e102125 25010227 PMC4092101
  66. [71]Demols A Le Moine O Desalle F Quertinmont E Van Laethem JL Deviere J 2000 CD4(+)T cells play an important role in acute experimental pancreatitis in mice Gastroenterology 118 582 90 10702210
  67. [72]Bedrosian AS Nguyen AH Hackman M Connolly MK Malhotra A Ibrahim J Cieza-Rubio NE Henning JR Barilla R Rehman A Pachter HL Medina-Zea MV Cohen SM Frey AB Acehan D Miller G 2011 Dendritic cells promote pancreatic viability in mice with acute pancreatitis Gastroenterology 141 1915 26 e1 14 21801698 PMC3202684
  68. [73]Denham W Yang J Fink G Denham D Carter G Ward K Norman J 1997 Gene targeting demonstrates additive detrimental effects of interleukin 1 and tumor necrosis factor during pancreatitis Gastroenterology 113 1741 6 9352880
  69. [74]Liou GY Doppler H Necela B Krishna M Crawford HC Raimondo M Storz P 2013 Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-kappaB and MMPs J Cell Biol 202 563 77 23918941 PMC3734091
  70. [75]Gukovsky I Gukovskaya A 2013 Nuclear factor-kappaB in pancreatitis: Jack-of-all-trades, but which one is more important? Gastroenterology 144 26 9 23164573 PMC6663071
  71. [76]Huang H Liu Y Daniluk J Gaiser S Chu J Wang H Li ZS Logsdon CD Ji B 2013 Activation of nuclear factor-kappaB in acinar cells increases the severity of pancreatitis in mice Gastroenterology 144 202 10 23041324 PMC3769090
  72. [77]Algul H Treiber M Lesina M Nakhai H Saur D Geisler F Pfeifer A Paxian S Schmid RM 2007 Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis J Clin Invest 117 1490 501 17525802 PMC1868784
  73. [78]Neuhofer P Liang S Einwachter H Schwerdtfeger C Wartmann T Treiber M Zhang H Schulz HU Dlubatz K Lesina M Diakopoulos KN Wormann S Halangk W Witt H Schmid RM Algul H 2013 Deletion of IkappaBalpha activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A Gastroenterology 144 192 201 23041330
  74. [79]Zhang H Neuhofer P Song L Rabe B Lesina M Kurkowski MU Treiber M Wartmann T Regner S Thorlacius H Saur D Weirich G Yoshimura A Halangk W Mizgerd JP Schmid RM Rose-John S Algul H 2013 IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality J Clin Invest 123 1019 31 23426178 PMC3582130
  75. [80]Cuzzocrea S Mazzon E Dugo L Centorrino T Ciccolo A McDonald MC de Sarro A Caputi AP Thiemermann C 2002 Absence of endogenous interleukin-6 enhances the inflammatory response during acute pancreatitis induced by cerulein in mice Cytokine 18 274 85 12161103
  76. [81]Chao KC Chao KF Chuang CC Liu SH 2006 Blockade of interleukin 6 accelerates acinar cell apoptosis and attenuates experimental acute pancreatitis in vivo Br J Surg 93 332 8 16392107
  77. [82]Shigekawa M Hikita H Kodama T Shimizu S Li W Uemura A Miyagi T Hosui A Kanto T Hiramatsu N Tatsumi T Takeda K Akira S Takehara T 2012 Pancreatic STAT3 protects mice against caerulein-induced pancreatitis via PAP1 induction Am J Pathol 181 2105 13 23064197
  78. [83]Afelik S Jensen J 2013 Notch signaling in the pancreas: patterning and cell fate specification WIREs Developmental Biology 2 531 44 24014421
  79. [84]Siveke JT Lubeseder-Martellato C Lee M Mazur PK Nakhai H Radtke F Schmid RM 2008 Notch signaling is required for exocrine regeneration after acute pancreatitis Gastroenterology 134 544 55 18242220
  80. [85]Kornberg TB 2014 The contrasting roles of primary cilia and cytonemes in Hh signaling Dev Biol PMC4163518 25072627
  81. [86]Gao T Zhou D Yang C Singh T Penzo-Mendez A Maddipati R Tzatsos A Bardeesy N Avruch J Stanger BZ 2013 Hippo signaling regulates differentiation and maintenance in the exocrine pancreas Gastroenterology 144 1543 53 53 e1 23454691 PMC3665616
  82. [87]George NM Day CE Boerner BP Johnson RL Sarvetnick NE 2012 Hippo signaling regulates pancreas development through inactivation of Yap Mol Cell Biol 32 5116 28 23071096 PMC3510525
  83. [88]Blaine SA Ray KC Anunobi R Gannon MA Washington MK Means AL 2010 Adult pancreatic acinar cells give rise to ducts but not endocrine cells in response to growth factor signaling Development 137 2289 96 20534672 PMC2889602
  84. [89]Ardito CM Gruner BM Takeuchi KK Lubeseder-Martellato C Teichmann N Mazur PK Delgiorno KE Carpenter ES Halbrook CJ Hall JC Pal D Briel T Herner A Trajkovic-Arsic M Sipos B Liou GY Storz P Murray NR Threadgill DW Sibilia M Washington MK Wilson CL Schmid RM Raines EW Crawford HC Siveke JT 2012 EGF receptor is required for KRAS-induced pancreatic tumorigenesis Cancer Cell 22 304 17 22975374 PMC3443395
  85. [90]Murtaugh LC Law AC Dor Y Melton DA 2005 Beta-Catenin is essential for pancreatic acinar but not islet development Development 132 4663 74 16192304
  86. [91]Wells JM Esni F Boivin GP Aronow BJ Stuart W Combs C Sklenka A Leach SD Lowy AM 2007 Wnt/beta-catenin signaling is required for development of the exocrine pancreas BMC Dev Biol 7 4 17222338 PMC1783845
  87. [92]Strom A Bonal C Ashery-Padan R Hashimoto N Campos ML Trumpp A Noda T Kido Y Real FX Thorel F Herrera PL 2007 Unique mechanisms of growth regulation and tumor suppression upon Apc inactivation in the pancreas Development 134 2719 25 17596282
  88. [93]Heiser PW Lau J Taketo MM Herrera PL Hebrok M 2006 Stabilization of {beta}-catenin impacts pancreas growth Development 133 2023 32 16611688
  89. [94]Valenta T Hausmann G Basler K 2012 The many faces and functions of beta-catenin EMBO J 31 2714 36 22617422 PMC3380220
  90. [95]Lin SL Li B Rao S Yeo EJ Hudson TE Nowlin BT Pei H Chen L Zheng JJ Carroll TJ Pollard JW McMahon AP Lang RA Duffield JS 2010 Macrophage Wnt7b is critical for kidney repair and regeneration Proc Natl Acad Sci U S A 107 4194 9 20160075 PMC2840080
  91. [96]Hale MA Swift GH Hoang CQ Deering TG Masui T Lee YK Xue J MacDonald RJ 2014 The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell-formation and acinar differentiation during pancreatic organogenesis Development PMC4197540 25063451
  92. [97]von Figura G Morris JPt Wright CV Hebrok M 2013 Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation Gut PMC3883808 23645620
  93. [98]Kopp JL von Figura G Mayes E Liu FF Dubois CL Morris JPt Pan FC Akiyama H Wright CV Jensen K Hebrok M Sander M 2012 Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma Cancer Cell 22 737 50 23201164 PMC3568632
  94. [99]Holmstrom SR Deering T Swift GH Poelwijk FJ Mangelsdorf DJ Kliewer SA MacDonald RJ 2011 LRH-1 and PTF1-L coregulate an exocrine pancreas-specific transcriptional network for digestive function Genes Dev 25 1674 9 21852532 PMC3165932
  95. [100]Pin CL Rukstalis JM Johnson C Konieczny SF 2001 The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity Journal of Cell Biology 155 519 30 11696558 PMC2198859
  96. [101]Kowalik AS Johnson CL Chadi SA Weston JY Fazio EN Pin CL 2007 Mice lacking the transcription factor Mist1 exhibit an altered stress response and increased sensitivity to caerulein-induced pancreatitis Am J Physiol Gastrointest Liver Physiol 292 G1123 32 17170023
  97. [102]Fukuda A Morris JPt Hebrok M 2012 Bmi1 is required for regeneration of the exocrine pancreas in mice Gastroenterology 143 821 31 e1 2 22609312 PMC3485080
  98. [103]Mallen-St Clair J Soydaner-Azeloglu R Lee KE Taylor L Livanos A Pylayeva-Gupta Y Miller G Margueron R Reinberg D Bar-Sagi D 2012 EZH2 couples pancreatic regeneration to neoplastic progression Genes Dev 26 439 44 22391448 PMC3305982
  99. [104]Sun L Mathews LA Cabarcas SM Zhang X Yang A Zhang Y Young MR Klarmann KD Keller JR Farrar WL 2013 Epigenetic regulation of SOX9 by the NF-kappaB signaling pathway in pancreatic cancer stem cells Stem Cells 31 1454 66 23592398 PMC3775871
  100. [105]Lee JM Lee YK Mamrosh JL Busby SA Griffin PR Pathak MC Ortlund EA Moore DD 2011 A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects Nature 474 506 10 21614002 PMC3150801
  101. [106]Sinha S Chen JK 2006 Purmorphamine activates the Hedgehog pathway by targeting Smoothened Nat Chem Biol 2 29 30 16408088
  102. [107]Pagliuca FW Melton DA 2013 How to make a functional beta-cell Development 140 2472 83 23715541 PMC3666377
  103. [108]Zhou Q Brown J Kanarek A Rajagopal J Melton DA 2008 In vivo reprogramming of adult pancreatic exocrine cells to beta-cells Nature 455 627 32 18754011 PMC9011918
  104. [109]Li W Nakanishi M Zumsteg A Shear M Wright C Melton DA Zhou Q 2014 In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes Elife (Cambridge) 3 e01846 PMC3977343 24714494
  105. [110]Baeyens L Lemper M Leuckx G De Groef S Bonfanti P Stange G Shemer R Nord C Scheel DW Pan FC Ahlgren U Gu G Stoffers DA Dor Y Ferrer J Gradwohl G Wright CV Van de Casteele M German MS Bouwens L Heimberg H 2014 Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice Nat Biotechnol 32 76 83 24240391 PMC4096987
  106. [111]De La OJP Emerson LL Goodman JL Froebe SC Illum BE Curtis AB Murtaugh LC 2008 Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia Proc Natl Acad Sci U S A 105 18907 12 19028876 PMC2585942
  107. [112]Murtaugh LC 2014 Pathogenesis of pancreatic cancer: lessons from animal models Toxicologic Pathology 42 217 28 24178582 PMC3926968
  108. [114]Fukuda A Wang SC Morris JPt Folias AE Liou A Kim GE Akira S Boucher KM Firpo MA Mulvihill SJ Hebrok M 2011 Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression Cancer Cell 19 441 55 21481787 PMC3075548
  109. [115]Lesina M Kurkowski MU Ludes K Rose-John S Treiber M Kloppel G Yoshimura A Reindl W Sipos B Akira S Schmid RM Algul H 2011 Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer Cancer Cell 19 456 69 21481788
  110. [116]Daniluk J Liu Y Deng D Chu J Huang H Gaiser S Cruz-Monserrate Z Wang H Ji B Logsdon CD 2012 An NF-kappaB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice J Clin Invest 122 1519 28 22406536 PMC3314459
  111. [117]Maier HJ Wagner M Schips TG Salem HH Baumann B Wirth T 2012 Requirement of NEMO/IKKgamma for effective expansion of KRAS-induced precancerous lesions in the pancreas Oncogene 22751123
  112. [118]Maniati E Bossard M Cook N Candido JB Emami-Shahri N Nedospasov SA Balkwill FR Tuveson DA Hagemann T 2011 Crosstalk between the canonical NF-kappaB and Notch signaling pathways inhibits Ppargamma expression and promotes pancreatic cancer progression in mice J Clin Invest 121 4685 99 22056382 PMC3225987
  113. [119]Hanlon L Avila JL Demarest RM Troutman S Allen M Ratti F Rustgi AK Stanger BZ Radtke F Adsay V Long F Capobianco AJ Kissil JL 2010 Notch1 functions as a tumor suppressor in a model of K-ras-induced pancreatic ductal adenocarcinoma Cancer Res 70 4280 6 20484026 PMC2880196

Authors
Murtaugh, L. C., & Keefe, M. D.
Affiliations
University of Utah (US)
ORCID
Murtaugh, L. Charles
Venue
Annual Review of Physiology
Publisher
Annual Reviews
Published
2015-02-10
Volume
77
Issue
1
Pages
229-249
ISSN
  • 0066-4278 (ISSN-L)
  • 1545-1585
DOI
10.1146/annurev-physiol-021014-071727
PMC
PMC4324082
OpenAlex
W2126268972
Cited by
197
References
120
Citations by year
2026: 12 · 2025: 18 · 2024: 16 · 2023: 16 · 2022: 17 · 2021: 27 · 2020: 23 · 2019: 18 · 2018: 18 · 2017: 11 · 2016: 11 · 2015: 10
FWCI
2.01
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Annual Review of Physiology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R21CA179453)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
pancreatitis, metaplasia, NF-κB signaling, pancreatic fibrosis, chronic pancreatitis, pancreatic cancer, acinar differentiation, cell-cell interactions, leukocytes, fibroblasts
MeSH terms
Animals, Cell Differentiation, Disease Models, Animal, Humans, Pancreatic Neoplasms, Pancreatitis, Regeneration, Signal Transduction, Pancreas, Exocrine, Acinar Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review