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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 -
Developmental Cell Sep 2022Three-dimensional mammary epithelial acini are a model for understanding how microenvironment-driven signaling coordinates cell behavior and tissue morphogenesis. In...
Three-dimensional mammary epithelial acini are a model for understanding how microenvironment-driven signaling coordinates cell behavior and tissue morphogenesis. In this issue of Developmental Cell, Ender et al. use live-cell imaging to capture dynamic spatiotemporal patterns of ERK activity that instruct cell migration and survival fates in developing acini.
Topics: Acinar Cells; Cell Movement; Epithelial Cells; Morphogenesis; Signal Transduction
PubMed: 36167056
DOI: 10.1016/j.devcel.2022.09.001 -
The American Journal of Surgical... May 2023Acinar cell carcinoma (ACC) is a rare and highly malignant pancreatic tumor. Owing to histologic similarity, ACC is often difficult to distinguish from other solid...
Acinar cell carcinoma (ACC) is a rare and highly malignant pancreatic tumor. Owing to histologic similarity, ACC is often difficult to distinguish from other solid medullary pancreatic tumors, particularly neuroendocrine neoplasm (NEN) and intraductal tubulopapillary neoplasm (ITPN). We aimed to identify new immunohistochemical markers commonly expressed in tumor cells with acinar cell differentiation and useful for both surgical and small biopsy specimens. Candidate molecules exclusively expressed in neoplastic or non-neoplastic acinar cells in pancreatic tissues with specific and available antibodies suitable for immunohistochemistry were selected. We selected carboxypeptidase A1 (CPA1), carboxypeptidase A2 (CPA2), and glycoprotein 2 (GP2), which were expressed in 100%, 100%, and 96% of cases, respectively, in ACC (n=27) or neoplasia with acinar cell differentiation, including mixed acinar-neuroendocrine carcinoma (n=9), mixed acinar-ductal carcinoma (n=3), pancreatoblastoma (n=4), and acinar cystic transformation (n=2), in the cytoplasm of tumor cells with a granular pattern. Both CPA2 and CPA1 were not expressed in any other tumors without acinar cell differentiation, including NEN (n=44), pancreatic ductal adenocarcinoma (n=44), and ITPN (n=4). GP2 was not expressed in these tumors except in rare cases, including 14% of NEN, 15% of intraductal papillary-mucinous neoplasm, 25% of intraductal oncocytic papillary neoplasm, 25% of ITPN, and 7% of pancreatic ductal adenocarcinoma, wherein a small proportion of tumor cells expressed GP2 in their apical cell membrane. NEN cases also showed cytoplasmic GP2 expression. Therefore, CPA2, CPA1, and potentially GP2 may act as ACC markers.
Topics: Humans; Carboxypeptidases A; Acinar Cells; Pancreatic Neoplasms; Pancreas; Carcinoma, Pancreatic Ductal; Carcinoma, Acinar Cell; Glycoproteins; Biomarkers, Tumor
PubMed: 36815573
DOI: 10.1097/PAS.0000000000002024 -
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 -
Nature Cell Biology Mar 2015Vital organs such as the pancreas and the brain lack the capacity for effective regeneration. To overcome this limitation, an emerging strategy consists of converting... (Review)
Review
Vital organs such as the pancreas and the brain lack the capacity for effective regeneration. To overcome this limitation, an emerging strategy consists of converting resident tissue-specific cells into the cell types that are lost due to disease by a process called in vivo lineage reprogramming. Here we discuss recent breakthroughs in regenerating pancreatic β-cells and neurons from various cell types, and highlight fundamental challenges that need to be overcome for the translation of in vivo lineage reprogramming into therapy.
Topics: Acinar Cells; Brain; Brain Diseases; Cell Differentiation; Cell Lineage; Cell- and Tissue-Based Therapy; Cellular Reprogramming; Humans; Insulin-Secreting Cells; Neuroglia; Neurons; Pancreas; Pancreatic Diseases; Regeneration
PubMed: 25720960
DOI: 10.1038/ncb3108 -
ACS Nano May 2024Severe acute pancreatitis (AP) is a life-threatening pancreatic inflammatory disease with a high mortality rate (∼40%). Existing pharmaceutical therapies in...
Inflammation and Acinar Cell Dual-Targeting Nanomedicines for Synergistic Treatment of Acute Pancreatitis via Ca Homeostasis Regulation and Pancreas Autodigestion Inhibition.
Severe acute pancreatitis (AP) is a life-threatening pancreatic inflammatory disease with a high mortality rate (∼40%). Existing pharmaceutical therapies in development or in clinical trials showed insufficient treatment efficacy due to their single molecular therapeutic target, poor water solubility, short half-life, limited pancreas-targeting specificity, etc. Herein, acid-responsive hollow mesoporous Prussian blue nanoparticles wrapped with neutrophil membranes and surface modified with the ,-dimethyl-1,3-propanediamine moiety were developed for codelivering membrane-permeable calcium chelator BAPTA-AM (BA) and trypsin activity inhibitor gabexate mesylate (Ga). In the AP mouse model, the formulation exhibited efficient recruitment at the inflammatory endothelium, -endothelial migration, and precise acinar cell targeting, resulting in rapid pancreatic localization and higher accumulation. A single low dose of the formulation (BA: 200 μg kg, Ga: 0.75 mg kg) significantly reduced pancreas function indicators to close to normal levels at 24 h, effectively restored the cell redox status, reduced apoptotic cell proportion, and blocked the systemic inflammatory amplified cascade, resulting in a dramatic increase in the survival rate from 58.3 to even 100%. Mechanistically, the formulation inhibited endoplasmic reticulum stress (IRE1/XBP1 and ATF4/CHOP axis) and restored impaired autophagy (Beclin-1/p62/LC3 axis), thereby preserving dying acinar cells and restoring the cellular "health status". This formulation provides an upstream therapeutic strategy with clinical translation prospects for AP management through synergistic ion homeostasis regulation and pancreatic autodigestion inhibition.
Topics: Animals; Pancreatitis; Acinar Cells; Mice; Homeostasis; Calcium; Nanomedicine; Inflammation; Nanoparticles; Pancreas; Mice, Inbred C57BL; Male; Humans
PubMed: 38652869
DOI: 10.1021/acsnano.4c00218 -
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 -
Journal of Visualized Experiments : JoVE Feb 2019The differentiation of acinar cells to ductal cells during pancreatitis and in the early development of pancreatic cancer is a key process that requires further study....
The differentiation of acinar cells to ductal cells during pancreatitis and in the early development of pancreatic cancer is a key process that requires further study. To understand the mechanisms regulating acinar-to-ductal metaplasia (ADM), ex vivo 3D culture and differentiation of primary acinar cells to ductal cells offers many advantages over other systems. With the technique herein, modulation of protein expression is simple and quick, requiring only one day to isolate, stimulate or virally infect, and begin culturing primary acinar cells to investigate the ADM process. In contrast to using basement membrane matrix, the seeding of acinar cell clusters in collagen I extracellular matrix, allows acinar cells to retain their acinar identity before manipulation. This is vital when testing the contribution of various components to the induction of ADM. Not only are the effects of cytokines or other ectopically administered factors testable through this technique, but the contribution of common mutations, increased protein expression, or knockdown of protein expression is testable via viral infection of primary acinar cells, using adenoviral or lentiviral vectors. Moreover, cells can be re-isolated from collagen or basement membrane matrix at the endpoint and analyzed for protein expression.
Topics: Acinar Cells; Cell Culture Techniques; Humans; Metaplasia; Pancreas; Pancreatic Ducts
PubMed: 30799859
DOI: 10.3791/59096 -
Apoptosis : An International Journal on... Feb 2016Pancreatic acinar cell death is the major pathophysiological change in early acute pancreatitis (AP), and the death modalities are important factors determining its... (Review)
Review
Pancreatic acinar cell death is the major pathophysiological change in early acute pancreatitis (AP), and the death modalities are important factors determining its progression and prognosis. During AP, acinar cells undergo two major modes of death, including necrosis and apoptosis. Acinar necrosis can lead to intensely local and systemic inflammatory responses, which both induce and aggravate the lesion. Necrosis has long been considered an unregulated, and passive cell death process. Since the effective interventions of necrosis are difficult to perform, its relevant studies have not received adequate attention. Necroptosis is a newly discovered cell death modality characterized by both necrosis and apoptosis, i.e., it is actively regulated by special genes, while has the typical morphological features of necrosis. Currently, necroptosis is gradually becoming an important topic in the fields of inflammatory diseases. The preliminary results from necroptosis in AP have confirmed the existence of acinar cell necroptosis, which may be a potential target for effectively regulating inflammatory injuries and improving its outcomes; however, the functional changes and mechanisms of necroptosis still require further investigation. This article reviewed the progress of necroptosis in AP to provide a reference for deeply understanding the pathogenic mechanisms of AP and identifying new therapeutic targets.
Topics: Acinar Cells; Animals; Apoptosis; Humans; Inflammasomes; Molecular Targeted Therapy; Necrosis; Pancreas; Pancreatitis, Acute Necrotizing; Signal Transduction
PubMed: 26514558
DOI: 10.1007/s10495-015-1192-3 -
Journal of Dental Research Nov 2015Understanding the intrinsic potential for renewal and regeneration within a tissue is critical for the rational design of reparative strategies. Maintenance of the... (Review)
Review
Understanding the intrinsic potential for renewal and regeneration within a tissue is critical for the rational design of reparative strategies. Maintenance of the salivary glands is widely thought to depend on the differentiation of stem cells. However, there is also new evidence that homeostasis of the salivary glands, like that of the liver and pancreas, relies on self-renewal of differentiated cells rather than a stem cell pool. Here, we review the evidence for both modes of turnover and consider the implications for the process of regeneration. We propose that the view of salivary glands as postmitotic and dependent on stem cells for renewal be revised to reflect the proliferative activity of acinar cells and their role in salivary gland homeostasis.
Topics: Acinar Cells; Animals; Cell Proliferation; Homeostasis; Humans; Regeneration; Salivary Glands; Stem Cells
PubMed: 26285812
DOI: 10.1177/0022034515599770