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Nature Reviews. Gastroenterology &... May 2017Acinar cells in the adult pancreas show high plasticity and can undergo transdifferentiation to a progenitor-like cell type with ductal characteristics. This process,... (Review)
Review
Acinar cells in the adult pancreas show high plasticity and can undergo transdifferentiation to a progenitor-like cell type with ductal characteristics. This process, termed acinar-to-ductal metaplasia (ADM), is an important feature facilitating pancreas regeneration after injury. Data from animal models show that cells that undergo ADM in response to oncogenic signalling are precursors for pancreatic intraepithelial neoplasia lesions, which can further progress to pancreatic ductal adenocarcinoma (PDAC). As human pancreatic adenocarcinoma is often diagnosed at a stage of metastatic disease, understanding the processes that lead to its initiation is important for the discovery of markers for early detection, as well as options that enable an early intervention. Here, the critical determinants of acinar cell plasticity are discussed, in addition to the intracellular and extracellular signalling events that drive acinar cell metaplasia and their contribution to development of PDAC.
Topics: Acinar Cells; Animals; Carcinoma, Pancreatic Ductal; Cellular Reprogramming; Disease Models, Animal; Humans; Mice; Pancreatic Neoplasms
PubMed: 28270694
DOI: 10.1038/nrgastro.2017.12 -
Gastroenterology May 2024Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplastic stroma surrounding most tumors. Activated stromal fibroblasts, namely cancer-associated...
BACKGROUND & AIMS
Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplastic stroma surrounding most tumors. Activated stromal fibroblasts, namely cancer-associated fibroblasts (CAFs), play a major role in PDAC progression. We analyzed whether CAFs influence acinar cells and impact PDAC initiation, that is, acinar-to-ductal metaplasia (ADM). ADM connection with PDAC pathophysiology is indicated, but not yet established. We hypothesized that CAF secretome might play a significant role in ADM in PDAC initiation.
METHODS
Mouse and human acinar cell organoids, acinar cells cocultured with CAFs and exposed to CAF-conditioned media, acinar cell explants, and CAF cocultures were examined by means of quantitative reverse transcription polymerase chain reaction, RNA sequencing, immunoblotting, and confocal microscopy. Data from liquid chromatography with tandem mass spectrometry analysis of CAF-conditioned medium and RNA sequencing data of acinar cells post-conditioned medium exposure were integrated using bioinformatics tools to identify the molecular mechanism for CAF-induced ADM. Using confocal microscopy, immunoblotting, and quantitative reverse transcription polymerase chain reaction analysis, we validated the depletion of a key signaling axis in the cell line, acinar explant coculture, and mouse cancer-associated fibroblasts (mCAFs).
RESULTS
A close association of acino-ductal markers (Ulex europaeus agglutinin 1, amylase, cytokeratin-19) and mCAFs (α-smooth muscle actin) in LSL-Kras; LSL-Trp53; Pdx1 (KPC) and LSL-Kras; Pdx1 (KC) autochthonous progression tumor tissue was observed. Caerulein treatment-induced mCAFs increased cytokeratin-19 and decreased amylase in wild-type and KC pancreas. Likewise, acinar-mCAF cocultures revealed the induction of ductal transdifferentiation in cell line, acinar-organoid, and explant coculture formats in WT and KC mice pancreas. Proteomic and transcriptomic data integration revealed a novel laminin α5/integrinα4/stat3 axis responsible for CAF-mediated acinar-to-ductal cell transdifferentiation.
CONCLUSIONS
Results collectively suggest the first evidence for CAF-influenced acino-ductal phenotypic switchover, thus highlighting the tumor microenvironment role in pancreatic carcinogenesis inception.
Topics: Animals; Humans; Mice; Acinar Cells; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Transdifferentiation; Coculture Techniques; Culture Media, Conditioned; Laminin; Metaplasia; Organoids; Pancreatic Neoplasms; Signal Transduction; Tumor Microenvironment
PubMed: 38154529
DOI: 10.1053/j.gastro.2023.12.018 -
Gastroenterology Jul 2022Mitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine...
BACKGROUND & AIMS
Mitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production.
METHODS
Two models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histologic and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in 2 distinct human pancreatitis cohorts.
RESULTS
Blocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss of ERRγ in primary acini abrogates messenger RNA expression and protein levels of mitochondrial oxidative phosphorylation complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, endoplasmic reticulum stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics, indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared with normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants for ERRγ that are associated with chronic pancreatitis.
CONCLUSIONS
Collectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.
Topics: Acinar Cells; Animals; Estrogens; Humans; Mice; Mice, Knockout; Pancreas; Pancreas, Exocrine; Pancreatitis, Chronic
PubMed: 35461826
DOI: 10.1053/j.gastro.2022.04.013 -
Cellular and Molecular Gastroenterology... 2022The pancreas consists of several specialized cell types that display a remarkable ability to alter cellular identity in injury, regeneration, and repair. The abundant... (Review)
Review
The pancreas consists of several specialized cell types that display a remarkable ability to alter cellular identity in injury, regeneration, and repair. The abundant cellular plasticity within the pancreas appears to be exploited in tumorigenesis, with metaplastic, dedifferentiation, and transdifferentiation processes central to the development of pancreatic intraepithelial neoplasia and intraductal papillary neoplasms, precursor lesions to pancreatic ductal adenocarcinoma. In the face of shifting cellular identity, the cell of origin of pancreatic cancer has been difficult to elucidate. However, with the extensive utilization of in vivo lineage-traced mouse models coupled with insights from human samples, it has emerged that the acinar cell is most efficiently able to give rise to both intraductal papillary neoplasms and pancreatic intraepithelial neoplasia but that acinar and ductal cells can undergo malignant transformation to pancreatic ductal adenocarcinoma. In this review, we discuss the cellular reprogramming that takes place in both the normal and malignant pancreas and evaluate the current state of evidence that implicate both the acinar and ductal cell as context-dependent origins of this deadly disease.
Topics: Acinar Cells; Animals; Carcinoma, Pancreatic Ductal; Cell Plasticity; Mice; Pancreas; Pancreatic Neoplasms
PubMed: 34352406
DOI: 10.1016/j.jcmgh.2021.07.014 -
Epigenomics 2015Acinar cells of the pancreas produce the majority of enzymes required for digestion and make up >90% of the cells within the pancreas. Due to a common developmental... (Review)
Review
Acinar cells of the pancreas produce the majority of enzymes required for digestion and make up >90% of the cells within the pancreas. Due to a common developmental origin and the plastic nature of the acinar cell phenotype, these cells have been identified as a possible source of β cells as a therapeutic option for Type I diabetes. However, recent evidence indicates that acinar cells are the main source of pancreatic intraepithelial neoplasias (PanINs), the predecessor of pancreatic ductal adenocarcinoma (PDAC). The conversion of acinar cells to either β cells or precursors to PDAC is dependent on reprogramming of the cells to a more primitive, progenitor-like phenotype, which involves changes in transcription factor expression and activity, and changes in their epigenetic program. This review will focus on the mechanisms that promote acinar cell reprogramming, as well as the factors that may affect these mechanisms.
Topics: Acinar Cells; Animals; Cell Differentiation; Cellular Reprogramming; Diabetes Mellitus, Type 1; Epigenesis, Genetic; Humans; Insulin-Secreting Cells; Mice; Pancreas; Pancreatic Diseases; Pancreatic Ducts; Pancreatic Neoplasms
PubMed: 25942535
DOI: 10.2217/epi.14.83 -
Cell Death & Disease Aug 2023Acinar cell dedifferentiation is one of the most notable features of acute and chronic pancreatitis. It can also be the initial step that facilitates pancreatic cancer...
Acinar cell dedifferentiation is one of the most notable features of acute and chronic pancreatitis. It can also be the initial step that facilitates pancreatic cancer development. In the present study, we further decipher the precise mechanisms and regulation using primary human cells and murine experimental models. Our RNAseq analysis indicates that, in both species, early acinar cell dedifferentiation is accompanied by multiple pathways related to cell survival that are highly enriched, and where SLC7A11 (xCT) is transiently upregulated. xCT is the specific subunit of the cystine/glutamate antiporter system x. To decipher its role, gene silencing, pharmacological inhibition and a knock-out mouse model were used. Acinar cells with depleted or reduced xCT function show an increase in ferroptosis relating to lipid peroxidation. Lower glutathione levels and more lipid ROS accumulation could be rescued by the antioxidant N-acetylcysteine or the ferroptosis inhibitor ferrostatin-1. In caerulein-induced acute pancreatitis in mice, xCT also prevents lipid peroxidation in acinar cells. In conclusion, during stress, acinar cell fate seems to be poised for avoiding several forms of cell death. xCT specifically prevents acinar cell ferroptosis by fueling the glutathione pool and maintaining ROS balance. The data suggest that xCT offers a druggable tipping point to steer the acinar cell fate in stress conditions.
Topics: Humans; Animals; Mice; Acinar Cells; Acute Disease; Ferroptosis; Pancreatitis; Reactive Oxygen Species; Glutamic Acid
PubMed: 37604805
DOI: 10.1038/s41419-023-06063-w -
Cell Death and Differentiation Sep 2021Maintenance of the pancreatic acinar cell phenotype suppresses tumor formation. Hence, repetitive acute or chronic pancreatitis, stress conditions in which the acinar...
Maintenance of the pancreatic acinar cell phenotype suppresses tumor formation. Hence, repetitive acute or chronic pancreatitis, stress conditions in which the acinar cells dedifferentiate, predispose for cancer formation in the pancreas. Dedifferentiated acinar cells acquire a large panel of duct cell-specific markers. However, it remains unclear to what extent dedifferentiated acini differ from native duct cells and which genes are uniquely regulating acinar cell dedifferentiation. Moreover, most studies have been performed on mice since the availability of human cells is scarce. Here, we applied a non-genetic lineage tracing method of human pancreatic exocrine acinar and duct cells that allowed cell-type-specific gene expression profiling by RNA sequencing. Subsequent to this discovery analysis, one transcription factor that was unique for dedifferentiated acinar cells was functionally characterized. RNA sequencing analysis showed that human dedifferentiated acinar cells expressed genes in "Pathways of cancer" with a prominence of MECOM (EVI-1), a transcription factor that was not expressed by duct cells. During mouse embryonic development, pre-acinar cells also transiently expressed MECOM and in the adult mouse pancreas, MECOM was re-expressed when mice were subjected to acute and chronic pancreatitis, conditions in which acinar cells dedifferentiate. In human cells and in mice, MECOM expression correlated with and was directly regulated by SOX9. Mouse acinar cells that, by genetic manipulation, lose the ability to upregulate MECOM showed impaired cell adhesion, more prominent acinar cell death, and suppressed acinar cell dedifferentiation by limited ERK signaling. In conclusion, we transcriptionally profiled the two major human pancreatic exocrine cell types, acinar and duct cells, during experimental stress conditions. We provide insights that in dedifferentiated acinar cells, cancer pathways are upregulated in which MECOM is a critical regulator that suppresses acinar cell death by permitting cellular dedifferentiation.
Topics: Acinar Cells; Animals; Cell Death; Cell Dedifferentiation; Disease Models, Animal; Humans; MDS1 and EVI1 Complex Locus Protein; Mice; Oncogenes; Signal Transduction
PubMed: 33762742
DOI: 10.1038/s41418-021-00771-6 -
Frontiers in Immunology 2022Acute pancreatitis (AP) is a common cause of a clinically acute abdomen. Crosstalk between acinar cells and leukocytes (especially macrophages) plays an important role...
Acute pancreatitis (AP) is a common cause of a clinically acute abdomen. Crosstalk between acinar cells and leukocytes (especially macrophages) plays an important role in the development of AP. However, the mechanism mediating the interaction between acinar cells and macrophages is still unclear. This study was performed to explore the role of acinar cell extracellular vesicles (EVs) in the crosstalk between acinar cells and macrophages involved in the pathogenesis of AP. EVs derived from caerulein-treated acinar cells induced macrophage infiltration and aggravated pancreatitis in an AP rat model. Further research showed that acinar cell-derived EV miR-183-5p led to M1 macrophage polarization by downregulating forkhead box protein O1 (FoxO1), and a dual-luciferase reporter assay confirmed that FoxO1 was directly inhibited by miR-183-5p. In addition, acinar cell-derived EV miR-183-5p reduced macrophage phagocytosis. Acinar cell-derived EV miR-183-5p promoted the pancreatic infiltration of M1 macrophages and increased local and systemic damage . Subsequently, miR-183-5p overexpression in macrophages induced acinar cell damage and trypsin activation, thus further exacerbating the disease. In clinical samples, elevated miR-183-5p levels were detected in serum EVs and positively correlated with the severity of AP. EV miR-183-5p might play an important role in the development of AP by facilitating M1 macrophage polarization, providing a new insight into the diagnosis and targeted management of pancreatitis. Graphical abstract of the present study. In our caerulein-induced AP model, miR-183-5p was upregulated in injured acinar cells and transported by EVs to macrophages. miR-183-5p could induce M1 macrophage polarization through downregulation of FoxO1 and the release of inflammatory cytokines, which could aggravate AP-related injuries. Therefore, a vicious cycle might exist between injured ACs and M1 macrophage polarization, which is fulfilled by EV-transported miR-183-5p, leading to sustainable and progressive AP-related injuries.
Topics: Acinar Cells; Acute Disease; Animals; Ceruletide; Down-Regulation; Extracellular Vesicles; Macrophages; MicroRNAs; Nerve Tissue Proteins; Pancreatitis; Rats
PubMed: 35911777
DOI: 10.3389/fimmu.2022.869207 -
British Journal of Pharmacology Sep 2021Pyroptosis is a lytic form of pro-inflammatory cell death characterised as caspase 1 dependent with canonical NLRP3 inflammasome-induced gasdermin D (GSDMD) activation....
BACKGROUND AND PURPOSE
Pyroptosis is a lytic form of pro-inflammatory cell death characterised as caspase 1 dependent with canonical NLRP3 inflammasome-induced gasdermin D (GSDMD) activation. We aimed to investigate the role of acinar pyroptotic cell death in pancreatic injury and systemic inflammation in AP.
EXPERIMENTAL APPROACH
Pancreatic acinar pyroptotic cell death pathway activation upon pancreatic toxin stimulation in vitro and in vivo was investigated. Effects of pharmacological (NLRP3 and caspase-1 inhibitors), constitutive (Nlrp3 , Casp1 and Gsdmd ) and acinar cell conditional (Pdx1 Nlrp3 and Pdx1 Gsdmd ) genetic inhibition on pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation were assessed using mouse AP models (caerulein, sodium taurocholate and l-arginine). Effects of Pdx1 Gsdmd versus myeloid conditional knockout (Lyz2 Gsdmd ) and Gsdmd versus receptor-interacting protein 3 (RIP3) inhibitor were compared in CER-AP.
KEY RESULTS
There was consistent pyroptotic acinar cell death upon pancreatic toxin stimulation both in vitro and in vivo, which was significantly reduced by pharmacological or genetic pyroptosis inhibition. Pdx1 Gsdmd but not Lyz2 Gsdmd mice showed significantly reduced pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation in caerulein-AP. Co-application of RIP3 inhibitor on Gsdmd mice further increased protection on caerulein-AP.
CONCLUSION AND IMPLICATIONS
This work demonstrates a critical role for NLRP3 inflammasome and GSDMD activation-mediated pyroptosis in acinar cells, linking pancreatic necrosis and systemic inflammation in AP. Targeting pyroptosis signalling pathways holds promise for specific AP therapy.
Topics: Acinar Cells; Acute Disease; Animals; Inflammasomes; Inflammation; Intracellular Signaling Peptides and Proteins; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Pancreatitis; Phosphate-Binding Proteins; Pyroptosis
PubMed: 33871879
DOI: 10.1111/bph.15499 -
Frontiers in Immunology 2022Acinar cell death and inflammatory response are two important events which determine the severity of acute pancreatitis (AP). Endoplasmic reticulum (ER) stress and...
Acinar cell death and inflammatory response are two important events which determine the severity of acute pancreatitis (AP). Endoplasmic reticulum (ER) stress and necroptosis are involved in this process, but the relationships between them remain unknown. Here, we analyzed the interaction between ER stress and necroptosis and the underlying mechanisms during AP. Experimental pancreatitis was induced in Balb/C mice by caerulein (Cae) and lipopolysaccharide (LPS) or L-arginine (L-Arg) , and pancreatic acinar cells were also used to follow cellular mechanisms during cholecystokinin (CCK) stimulation . AP severity was assessed by serum amylase, lipase levels and histological examination. Changes in ER stress, trypsinogen activation and necroptosis levels were analyzed by western blotting, enzyme-linked immunosorbent assay (ELISA), adenosine triphosphate (ATP) analysis or lactate dehydrogenase (LDH) assay. The protein kinase C (PKC)α -mitogen-activated protein kinase (MAPK) -cJun pathway and cathepsin B (CTSB) activation were evaluated by western blotting. Activating protein 1 (AP-1) binding activity was detected by electrophoretic mobility shift assay (EMSA). We found that ER stress is initiated before necroptosis in CCK-stimulated acinar cells . Inhibition of ER stress by 4-phenylbutyrate (4-PBA) can significantly alleviate AP severity both in two AP models . 4-PBA markedly inhibited ER stress and necroptosis of pancreatic acinar cells both and . Mechanistically, we found that 4-PBA significantly reduced CTSB maturation and PKCα-JNK-cJun pathway -mediated AP-1 activation during AP. Besides, CTSB inhibitor CA074Me markedly blocked PKCα-JNK-cJun pathway -mediated AP-1 activation and necroptosis in AP. However, pharmacologic inhibition of trypsin activity with benzamidine hydrochloride had no effect on PKCα-JNK-cJun pathway and necroptosis in CCK-stimulated pancreatic acinar cells. Furthermore, SR11302, the inhibitor of AP-1, significantly lowered tumor necrosis factor (TNF) α levels, and its subsequent receptor interacting protein kinases (RIP)3 and phosphorylated mixed lineagekinase domain-like (pMLKL) levels, ATP depletion and LDH release rate in CCK-stimulated pancreatic acinar cells. To sum up, all the results indicated that during AP, ER stress promoted pancreatic acinar cell necroptosis through CTSB maturation, thus induced AP-1 activation and TNFα secretion PKCα-JNK-cJun pathway, not related with trypsin activity. These findings provided potential therapeutic target and treatment strategies for AP or other cell death-related diseases.
Topics: Acinar Cells; Acute Disease; Adenosine Triphosphate; Animals; Cathepsin B; Endoplasmic Reticulum Stress; Mice; Mice, Inbred BALB C; Necroptosis; Pancreatitis; Protein Kinase C-alpha; Transcription Factor AP-1; Trypsin
PubMed: 36059491
DOI: 10.3389/fimmu.2022.968639