Transgenic Expression of a Single Transcription Factor Pdx1 Induces Transdifferentiation of Pancreatic Acinar Cells to Endocrine Cells in Adult Mice

Replacement of the exocrine parenchyma by fibrous tissue is a main characteristic of chronic pancreatitis. Understanding the mechanisms of pancreatic fibrogenesis is critical for the development of preventive and therapeutic interventions. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin synthesis, is expressed in patients with chronic pancreatitis. However, it is unknown whether COX-2 can cause chronic pancreatitis. To investigate the roles of pancreatic acinar COX-2 in fibrogenesis and the development of chronic pancreatitis, COX-2 was ectopically expressed specifically in pancreatic acinar cells in transgenic mice. Histopathological changes and expression levels of several profibrogenic factors related to chronic pancreatitis were evaluated. COX-2 was expressed in the pancreas of the transgenic mice, as detected by Western blot analysis. Immunohistochemical staining showed COX-2 was specifically expressed in pancreatic acinar cells. COX-2 expression led to progressive changes in the pancreas, including pancreas megaly, persistent inflammation, collagen deposition, and acinar-to-ductal metaplasia. Quantitative RT-PCR and immunostaining showed that profibrogenic factors were upregulated and pancreatic stellate cells were activated in the COX-2 transgenic mice. Expression of COX-2 in pancreatic acinar cells is sufficient to induce chronic pancreatitis. Targeting this pathway may be valuable in the prevention of chronic pancreatitis. NEW & NOTEWORTHY COX-2 expression is observed in pancreatic tissues of human chronic pancreatitis. In this study, we showed that COX-2 expression caused the development of chronic pancreatitis in transgenic mice, supporting the idea that COX-2 inhibition may be an effective preventive and therapeutic strategy.

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TRANSCRIPTION FACTOR PROFILING OF PANCREATIC ACINAR CELLS FOLLOWING TNF-α INDUCTION OF ACUTE PANCREATITIS.

Shock ◽

10.1097/00024382-200306001-00057 ◽

2003 ◽

Vol 19 (Supplement) ◽

pp. 20

Author(s):

L. Vona-Davis ◽

K. Magabo ◽

B. Jackson ◽

T. Evans ◽

D. Riggs ◽

...

Keyword(s):

Acute Pancreatitis ◽

Transcription Factor ◽

Acinar Cells ◽

Pancreatic Acinar Cells ◽

Tnf Α

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Increased Chromogranin A–Positive Hormone-Negative Cells in Chronic Pancreatitis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-01562 ◽

2018 ◽

Vol 103 (6) ◽

pp. 2126-2135 ◽

Cited By ~ 7

Author(s):

Abu Saleh Md Moin ◽

Megan Cory ◽

Jennifer Choi ◽

Allison Ong ◽

Sangeeta Dhawan ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Chromogranin A ◽

Endocrine Cells ◽

Acinar Cells ◽

Pancreatic Acinar Cells ◽

Cell Regeneration ◽

Inflammation Marker ◽

Β Cells ◽

Cell Frequency ◽

Endogenous Expression

Abstract Context Chronic pancreatitis (CP) is characterized by inflammation, fibrosis, and a loss of pancreatic acinar cells, which can result in exocrine and eventually endocrine deficiency. Pancreatitis has been reported to induce formation of new endocrine cells (neogenesis) in mice. Our recent data have implicated chromogranin A–positive hormone-negative (CPHN) cells as potential evidence of neogenesis in humans. Objective We sought to establish if CPHN cells were more abundant in CP in humans. Design, Setting, and Participants We investigated the frequency and distribution of CPHN cells and the expression of the chemokine C-X-C motif ligand 10 (CXCL10) and its receptor chemokine C-X-C motif receptor 3 in pancreas of nondiabetic subjects with CP. Results CPHN cell frequency in islets was increased sevenfold in CP [2.1% ± 0.67% vs 0.35% ± 0.09% CPHN cells in islets, CP vs nonpancreatitis (NP), P < 0.01], as were the CPHN cells found as scattered cells in the exocrine areas (17.4 ± 2.9 vs 4.2 ± 0.6, CP vs NP, P < 0.001). Polyhormonal endocrine cells were also increased in CP (2.7 ± 1.2 vs 0.1 ± 0.04, CP vs NP, % of polyhormonal cells of total endocrine cells, P < 0.01), as was expression of CXCL10 in α and β cells. Conclusion There is increased islet endogenous expression of the inflammation marker CXCL10 in islets in the setting of nondiabetic CP and an increase in polyhormonal (insulin-glucagon expressing) cells. The increase in CPHN cells in CP, often in a lobular distribution, may indicate foci of attempted endocrine cell regeneration.

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Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors

Endocrine Related Cancer ◽

10.1677/erc-08-0127 ◽

2009 ◽

Vol 16 (1) ◽

pp. 267-279 ◽

Cited By ~ 24

Author(s):

Yu-Cheng Wang ◽

Emerick Gallego-Arteche ◽

Gioia Iezza ◽

Xiaochen Yuan ◽

Mary R Matli ◽

...

Keyword(s):

Transcription Factor ◽

Endocrine Cells ◽

Homeodomain Transcription Factor ◽

Normal Tissues ◽

Adult Mice ◽

The Central Nervous System ◽

Normal Intestine ◽

Marker Expression ◽

Glucagon Like Peptide 1 ◽

Novel Target

The homeodomain transcription factor NKX2.2 is necessary for neuroendocrine (NE) differentiation in the central nervous system and pancreas. NE tumors derived from the gut are defined by their NE phenotype, which is used for diagnosis and contributes to tumorigenicity. We hypothesized that NKX2.2 is important for NE differentiation in normal and neoplastic gut. NKX2.2 and NE marker expression was investigated in the small intestine of embryonic and adult mice using immunofluorescence (IF). To determine the role of NKX2.2 in NE differentiation of the intestine, the phenotype of Nkx2.2 (−/−) mice was examined by IF and real-time (RT)-PCR. NKX2.2 and NE marker expression in human NE tumors of the gut and normal tissues were evaluated by immunohistochemistry and qRT-PCR. NKX2.2 expression was detected in the intervillus/crypt regions of embryonic and adult mouse intestine. Co-expression of Nkx2.2 with neurogenin3 (NEUROG3) and hormones was observed in the adult intestinal crypt compartment, suggesting NKX2.2 functions in NEUROG3-positive endocrine progenitors and newly differentiated endocrine cells. In the intestine of Nkx2.2 (−/−) mice, we found a dramatic reduction in the number of cells producing numerous hormones, such as serotonin, gastrin, cholecystokinin, somatostatin, glucagon-like peptide 1 (GLP-1), and secretin, but an increase in cells producing ghrelin. NKX2.2 was expressed in most (24 of 29) human NE tumors derived from diverse primary sites. We conclude NKX2.2 functions in immature endocrine cells to control NE differentiation in normal intestine and is expressed in most NE tumors of the gut, and is therefore a novel target of diagnosis for patients with gastrointestinal NE tumors.

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TRANSGENIC EXPRESSION OF THE NF??B SUBUNIT p65 IN PANCREATIC ACINAR CELLS OF TRANSGENIC MICE INCREASES THE SEVERITY OF ACUTE PANCREATITIS

Pancreas ◽

10.1097/01.mpa.0000193691.05954.1c ◽

2005 ◽

Vol 31 (4) ◽

pp. 448

Author(s):

Baoan Ji ◽

Jian Song ◽

Craig D Logsdon

Keyword(s):

Acute Pancreatitis ◽

Transgenic Mice ◽

Acinar Cells ◽

Pancreatic Acinar Cells ◽

Transgenic Expression ◽

B Subunit

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SEC23B is required for pancreatic acinar cell function in adult mice

Molecular Biology of the Cell ◽

10.1091/mbc.e17-01-0001 ◽

2017 ◽

Vol 28 (15) ◽

pp. 2146-2154 ◽

Cited By ~ 7

Author(s):

Rami Khoriaty ◽

Nancy Vogel ◽

Mark J. Hoenerhoff ◽

M. Dolors Sans ◽

Guojing Zhu ◽

...

Keyword(s):

Acinar Cell ◽

Cell Function ◽

Acinar Cells ◽

Cell Loss ◽

Normal Function ◽

Pancreatic Acinar Cell ◽

Pancreatic Acinar Cells ◽

Total Protein Content ◽

Pancreatic Cell ◽

Adult Mice

Mice with germline absence of SEC23B die perinatally, exhibiting massive pancreatic degeneration. We generated mice with tamoxifen-inducible, pancreatic acinar cell–specific Sec23b deletion. Inactivation of Sec23b exclusively in the pancreatic acinar cells of adult mice results in decreased overall pancreatic weights from pancreatic cell loss (decreased pancreatic DNA, RNA, and total protein content), as well as degeneration of exocrine cells, decreased zymogen granules, and alterations in the endoplasmic reticulum (ER), ranging from vesicular ER to markedly expanded cisternae with accumulation of moderate-density content or intracisternal granules. Acinar Sec23b deletion results in induction of ER stress and increased apoptosis in the pancreas, potentially explaining the loss of pancreatic cells and decreased pancreatic weight. These findings demonstrate that SEC23B is required for normal function of pancreatic acinar cells in adult mice.

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Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00431.2009 ◽

2010 ◽

Vol 298 (4) ◽

pp. G518-G524 ◽

Cited By ~ 14

Author(s):

Joelle M.-J. Romac ◽

Masaki Ohmuraya ◽

Cathy Bittner ◽

M. Faraz Majeed ◽

Steven R. Vigna ◽

...

Keyword(s):

Trypsin Inhibitor ◽

Survival Rates ◽

Acinar Cells ◽

Threshold Level ◽

Protective Role ◽

Trypsin Inhibitors ◽

Pancreatic Acinar Cells ◽

Wild Type ◽

Transgenic Expression ◽

Pancreatic Trypsin Inhibitor

Endogenous trypsin inhibitors are synthesized, stored, and secreted by pancreatic acinar cells. It is believed that they play a protective role in the pancreas by inhibiting trypsin within the cell should trypsinogen become prematurely activated. Rodent trypsin inhibitors are highly homologous to human serine protease inhibitor Kazal-type 1 (SPINK1). The mouse has one pancreatic trypsin inhibitor known as SPINK3, and the rat has two trypsin inhibitors commonly known as pancreatic secretory trypsin inhibitors I and II (PSTI-I and -II). Rat PSTI-I is a 61-amino acid protein that shares 65% sequence identity with mouse SPINK3. It was recently demonstrated that mice with genetic deletion of the Spink3 gene ( Spink3−/− ) do not survive beyond 15 days and lack normal pancreata because of pancreatic autophagy. We have shown that targeted transgenic expression of the rat Psti1 gene to acinar cells in mice [ TgN(Psti1)] protects mice against caerulein-induced pancreatitis. To determine whether the autophagic phenotype and lethality in Spink3−/− mice were due to lack of pancreatic trypsin inhibitor, we conducted breeding studies with Spink3+/− heterozygous mice and TgN(Psti1) mice. We observed that, whereas Spink3+/+, Spink3+/−, and Spink3−/− /TgN(Psti1) mice had similar survival rates, no Spink3−/− mice survived longer than 1 wk. The level of expression of SPINK3 protein in acini was reduced in heterozygote mice compared with wild-type mice. Furthermore, endogenous trypsin inhibitor capacity was reduced in the pancreas of heterozygote mice compared with wild-type or knockout mice rescued with the rat Psti1 gene. Surprisingly, the lesser amount of SPINK3 present in the pancreata of heterozygote mice did not predispose animals to increased susceptibility to caerulein-induced acute pancreatitis. We propose that a threshold level of expression is sufficient to protect against pancreatitis.

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Pancreatic secretory trypsin inhibitor I reduces the severity of chronic pancreatitis in mice overexpressing interleukin-1β in the pancreas

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00287.2011 ◽

2012 ◽

Vol 302 (5) ◽

pp. G535-G541 ◽

Cited By ~ 7

Author(s):

Joelle M.-J. Romac ◽

Rafiq A. Shahid ◽

Steve S. Choi ◽

Gamze F. Karaca ◽

Christoph B. Westphalen ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Trypsin Inhibitor ◽

Acinar Cells ◽

Cell Loss ◽

Pancreatic Acinar Cells ◽

Trypsin Inhibitor Activity ◽

Myeloperoxidase Activity ◽

Trypsin Activity ◽

Pancreatic Secretory Trypsin Inhibitor ◽

Transgenic Expression

IL-1β is believed to play a pathogenic role in the development of pancreatitis. Expression of human IL-1β in pancreatic acinar cells produces chronic pancreatitis, characterized by extensive intrapancreatic inflammation, atrophy, and fibrosis. To determine if activation of trypsinogen is important in the pathogenesis of chronic pancreatitis in this model, we crossed IL-1β transgenic [Tg( IL1β)] mice with mice expressing a trypsin inhibitor that is normally produced in rat pancreatic acinar cells [pancreatic secretory trypsin inhibitor (PTSI) I]. We previously demonstrated that transgenic expression of PSTI-I [Tg( Psti1)] increased pancreatic trypsin inhibitor activity by 190%. Tg( IL1β) mice were found to have marked pancreatic inflammation, characterized by histological changes, including acinar cell loss, inflammatory cell infiltration, and fibrosis, as well as elevated myeloperoxidase activity and elevated pancreatic trypsin activity, as early as 6 wk of age. In contrast to Tg( IL1β) mice, pancreatitis was significantly less severe in dual-transgenic [Tg( IL1β)-Tg( Psti1)] mice expressing IL-1β and PSTI-I in pancreatic acinar cells. These findings indicate that overexpression of PSTI-I reduces the severity of pancreatitis and that pancreatic trypsin activity contributes to the pathogenesis of an inflammatory model of chronic pancreatitis.

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