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

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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Faculty Opinions recommendation of Preexisting pancreatic acinar cells contribute to acinar cell, but not islet beta cell, regeneration.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1081013.533973 ◽

2007 ◽

Author(s):

Raghavendra Mirmira

Keyword(s):

Beta Cell ◽

Acinar Cell ◽

Acinar Cells ◽

Pancreatic Acinar Cells ◽

Cell Regeneration ◽

Beta Cell Regeneration ◽

Islet Beta Cell

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Transgenic expression of cyclooxygenase-2 in pancreatic acinar cells induces chronic pancreatitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00096.2018 ◽

2019 ◽

Vol 316 (1) ◽

pp. G179-G186

Author(s):

Haojie Huang ◽

Jiaxiang Chen ◽

Lisi Peng ◽

Yao Yao ◽

Defeng Deng ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Transgenic Mice ◽

Fibrous Tissue ◽

Acinar Cells ◽

Cyclooxygenase 2 ◽

Therapeutic Interventions ◽

Pancreatic Stellate Cells ◽

Pancreatic Acinar Cells ◽

Transgenic Expression ◽

Cox 2

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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Structural changes in pancreatic acinar cells and β-cells of rat fed with genetically modified corn

Journal of Experimental and Clinical Anatomy ◽

10.4103/1596-2393.200918 ◽

2016 ◽

Vol 15 (2) ◽

pp. 77 ◽

Cited By ~ 1

Author(s):

El SayedAly Mohamed Metwally ◽

FardousSoror Karawya

Keyword(s):

Structural Changes ◽

Genetically Modified ◽

Acinar Cells ◽

Pancreatic Acinar Cells ◽

Β Cells

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Icariin Promote Stem Cells Regeneration and Repair Acinar Cells in L-arginine / Radiation -Inducing Chronic Pancreatitis in Rats

Dose-Response ◽

10.1177/1559325820970810 ◽

2020 ◽

Vol 18 (4) ◽

pp. 155932582097081

Author(s):

Enas M. Moustafa ◽

Fatma S. M. Moawed ◽

Gehan R. Abdel-Hamid

Keyword(s):

Chronic Pancreatitis ◽

Hedgehog Signaling ◽

Histopathological Examination ◽

Acinar Cells ◽

Pancreatic Acinar Cells ◽

Myeloperoxidase Activity ◽

Significant Amelioration ◽

Gli 1 ◽

Patched 1

Objective: Chronic Pancreatitis (CP) is a multifactorial disease. It was characterized by severe inflammation and acinar cell destruction. Thus, the present study was initiated to evaluating the ability of bone marrow-based mesenchymal stem cell (MSCs) combined with Icariin to restore and regenerate acinar cells in the pancreas of rats suffering chronic pancreatitis. Methods: Chronic pancreatitis was induced in rats via both L-arginine plus radiation, repeated L-arginine injection (2.5g/Kg body-weight, 1, 4,7,10,13,16,19 days), then, on day 21, rats were exposed to a single dose of gamma-radiation (6 Gy), which exacerbate injury of pancreatic acinar cells. One day after irradiation, rats were treated with either MSCs (1 × 107 /rat, once, tail vein injection) labeled PKH26 fluorescent linker dye and/or Icariin (100 mg/Kg, daily, orally) for 8 weeks. Results: Icariin promotes MSCs proliferation boosting its productivity in vitro. MSCs, and/or icariin treatments has regulated molecular factors TGF-β/PDGF and promoted the regeneration of pancreatic tissues by releasing PDX-1 and MafA involved in the recruitment of stem/progenitor cell in the tissue, and confirmed by histopathological examination. Moreover, a significant decrease in IL-8 and TNF-α cytokines with significant amelioration of myeloperoxidase activity were noted. As well as, reduction in MCP-1 and collagen type-1 levels along with Hedgehog signaling down-regulating expression in such cells, Patched-1, Smoothened, and GLi-1. Conclusion: The potent bioactive therapeutic Icariin combined with MSCs induces a significantly greater improvement, compared to each therapy alone.

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794e Lack of Basal Autophagy in Pancreatic Acinar Cells Develops Chronic Pancreatitis in Mice

Gastroenterology ◽

10.1016/s0016-5085(14)60487-x ◽

2014 ◽

Vol 146 (5) ◽

pp. S-138

Author(s):

Kiyoshi Iwahashi ◽

Hayato Hikita ◽

Minoru Shigekawa ◽

Kenji Ikezawa ◽

Satoshi Shimizu ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Acinar Cells ◽

Pancreatic Acinar Cells

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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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p.E152K-STIM1 mutation deregulates Ca2+ signaling contributing to chronic pancreatitis

10.1101/2020.01.22.916254 ◽

2020 ◽

Author(s):

Miguel Burgos ◽

Reginald Philippe ◽

Fabrice Antigny ◽

Paul Buscaglia ◽

Emmanuelle Masson ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Chronic Pancreatitis ◽

Acinar Cells ◽

Pancreatic Acinar Cell ◽

Pancreatic Acinar Cells ◽

Endoplasmic Reticulum Calcium ◽

Store Operated Calcium Entry ◽

Intracellular Ca ◽

Intracellular Changes ◽

Main Regulator

ABSTRACTSince deregulation of intracellular Ca2+ can lead to intracellular trypsin activation and STIM1 (stromal interaction molecule-1) protein is the main regulator of Ca2+ homeostasis in pancreatic acinar cells, we explored the Ca2+ signaling in 37 STIM1 variants found in three pancreatitis patient cohorts. Extensive functional analysis of one particular variant, p.E152K, identified in three patients, provided a plausible link between dysregulated Ca2+ signaling within pancreatic acinar cells and chronic pancreatitis susceptibility. Specifically, p.E152K, located within the STIM1 EF-hand and sterile α-motif domain, increased the release of Ca2+ from the endoplasmic reticulum in patient-derived fibroblasts and transfected HEK293T cells. This event was mediated by altered STIM1-sarco/endoplasmic reticulum calcium transport ATPase (SERCA) interactions and enhanced SERCA pump activity leading to increased Store Operated Calcium Entry (SOCE). In the pancreatic AR42J cells expressing the p.E152K variant, Ca2+-signaling perturbations correlated with defects in trypsin activation and secretion, and increased cytotoxicity after cholecystokinin stimulation.Summary statementp.E152K-STIM1 variant found in pancreatitis patients leads to intracellular changes in calcium homeostasis through SERCA interaction, enabling intracellular trypsin activation and pancreatic acinar cell death.

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In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes

eLife ◽

10.7554/elife.01846 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 79

Author(s):

Weida Li ◽

Mio Nakanishi ◽

Adrian Zumsteg ◽

Matthew Shear ◽

Christopher Wright ◽

...

Keyword(s):

Transcription Factors ◽

Regenerative Medicine ◽

Acinar Cells ◽

Pancreatic Acinar Cells ◽

Specific Cell ◽

Β Cells ◽

Β Cell ◽

Cell Induction ◽

Direct Lineage Conversion

Direct lineage conversion of adult cells is a promising approach for regenerative medicine. A major challenge of lineage conversion is to generate specific cell subtypes. The pancreatic islets contain three major hormone-secreting endocrine subtypes: insulin+ β-cells, glucagon+ α-cells, and somatostatin+ δ-cells. We previously reported that a combination of three transcription factors, Ngn3, Mafa, and Pdx1, directly reprograms pancreatic acinar cells to β-cells. We now show that acinar cells can be converted to δ-like and α-like cells by Ngn3 and Ngn3+Mafa respectively. Thus, three major islet endocrine subtypes can be derived by acinar reprogramming. Ngn3 promotes establishment of a generic endocrine state in acinar cells, and also promotes δ-specification in the absence of other factors. δ-specification is in turn suppressed by Mafa and Pdx1 during α- and β-cell induction. These studies identify a set of defined factors whose combinatorial actions reprogram acinar cells to distinct islet endocrine subtypes in vivo.

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Impaired autophagy increases susceptibility to endotoxin-induced chronic pancreatitis

Cell Death and Disease ◽

10.1038/s41419-020-03050-3 ◽

2020 ◽

Vol 11 (10) ◽

Author(s):

L. Xia ◽

Z. Xu ◽

X. Zhou ◽

F. Bergmann ◽

N. Grabe ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Lethal Dose ◽

Acinar Cells ◽

Pancreatic Injury ◽

Pancreatic Tissue ◽

Pancreatic Acinar Cells ◽

Chromogenic Assay ◽

Enhanced Expression ◽

Metabolic Endotoxemia

Abstract Chronic pancreatitis (CP) is associated with elevated plasma levels of bacterial lipopolysaccharide (LPS) and we have demonstrated reduced acinar cell autophagy in human CP tissue. Therefore, we investigated the role of autophagy in experimental endotoxin-induced pancreatic injury and aimed to identify LPS in human CP tissue. Pancreatic Atg7-deficient mice were injected with a single sub-lethal dose of LPS. Expression of autophagy, apoptosis, necroptosis, and inflammatory markers was determined 3 and 24 h later utilizing immunoblotting and immunofluorescence. The presence of LPS in pancreatic tissue from mice and from patients and healthy controls was determined using immunohistochemistry, immunoblots, and chromogenic assay. Mice lacking pancreatic autophagy exhibited local signs of inflammation and were particularly sensitive to the toxic effect of LPS injection as compared to control mice. In response to LPS, Atg7Δpan mice exhibited enhanced vacuolization of pancreatic acinar cells, increase in TLR4 expression coupled to enhanced expression of NF-κΒ, JNK, and pro-inflammatory cytokines by acinar cells and enhanced infiltration by myeloid cells (but not Atg7F/F controls). Cell death was enhanced in Atg7Δpan pancreata, but only necroptosis and trypsin activation was further amplified following LPS injection along with elevated pancreatic LPS. The presence of LPS was identified in the pancreata from all 14 CP patients examined but was absent in the pancreata from all 10 normal controls. Altogether, these results support a potential role for metabolic endotoxemia in the pathogenesis of CP. Moreover, the evidence also supports the notion that autophagy plays a major cytoprotective and anti-inflammatory role in the pancreas, and blunting metabolic endotoxemia-induced CP.

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