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Luc Bouwens - One of the best experts on this subject based on the ideXlab platform.
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MECOM permits pancreatic acinar Cell dedifferentiation avoiding Cell death under stress conditions
Cell Death & Differentiation, 2021Co-Authors: Elyne Backx, Elke Wauters, Jonathan Baldan, Mathias Van Bulck, Ellis Michiels, Yves Heremans, Diedert Luc De Paep, Mineo Kurokawa, Susumu Goyama, Luc BouwensAbstract: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.
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mecom permits pancreatic acinar Cell dedifferentiation avoiding Cell death under stress conditions
bioRxiv, 2020Co-Authors: Elyne Backx, Luc Bouwens, Elke Wauters, Jonathan Baldan, Mathias Van Bulck, Ellis Michiels, Yves Heremans, Diedert Luc De Paep, Mineo Kurokawa, Susumu GoyamaAbstract:ABSTRACT 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 in mouse since the availability of human Cells is scarce. Here, we applied a non-genetic lineage tracing method in our culture model of human pancreatic Exocrine 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 using in vitro and in vivo genetic loss-of-function experimental models. RNA sequencing analysis showed that human dedifferentiated acinar Cells expressed genes in ‘Pathways of cancer’ with prominence of the transcription factor MECOM (EVI-1) that was absent from duct Cells. During mouse embryonic development, pre-acinar Cells transiently expressed MECOM and MECOM was re-expressed in experimental in vivo models of acute and chronic pancreatitis in vivo, conditions in which acinar Cells dedifferentiate. MECOM expression correlated with and was directly regulated by SOX9. MECOM loss-of-function in mouse acinar Cells in vitro and in vivo impaired Cell adhesion resulting in more prominent acinar Cell death and suppressed acinar Cell dedifferentiation by limiting 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.
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expression of the notch signaling pathway and effect on Exocrine Cell proliferation in adult rat pancreas
American Journal of Pathology, 2006Co-Authors: Ilse Rooman, Jessy Lardon, Nele De Medts, Luc Baeyens, Saskia De Breuck, Harry Heimberg, Luc BouwensAbstract:When pancreatic tissue is injured after duct obstruction, acinoductal metaplasia is observed. Similar metaplastic changes occur when Exocrine pancreatic Cells are isolated and cultured. We demonstrate that under these experimental conditions the Exocrine acinar Cells lose their differentiated characteristics: expression of the acinar transcription factors p48/Ptf1α and Mist1 is decreased or lost, whereas expression of the embryonic transcription factor Pdx1 is increased. The receptors Notch1 and Notch2, members of the DSL family of Notch ligands, and the target genes in the Notch-signaling pathway Hes1, Hey1, and Hey2 become strongly up-regulated. We noted also reduced expression of Sel1L, a Notch repressor that is normally highly expressed in Exocrine pancreas. Stimulation of Notch by its ligand Jagged1 diminished the proliferation of cultured metaplastic Exocrine Cells. Chemical inhibition of Notch signaling resulted in increased proliferation and induction of the Cell-cycle regulator p21Cip1. This effect seems to be Hes1-independent and mainly coincides with decreased Hey1 and Hey2 mRNA expression. In conclusion, we demonstrate that during acinoductal metaplasia the Notch-signaling pathway is activated concomitantly with changes in transcription factor expression of pancreatic acinar Cells. In addition, we show that Notch signaling is implicated in the suppression of proliferation of these metaplastic Exocrine Cells. The latter may be important in protection from neoplastic transformation.
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Exocrine Cell transdifferentiation in dexamethasone treated rat pancreas
Virchows Archiv, 2004Co-Authors: Jessy Lardon, Niki Huyens, Ilse Rooman, Luc BouwensAbstract:Injured pancreatic tissue, for example, after duct ligation, undergoes remodeling, which involves the replacement of Exocrine acini by duct-like structures. This acinoductal metaplasia is probably at least partly due to transdifferentiation of amylase-positive, cytokeratin-20 (CK20)-negative acinar Cells into amylase-negative, CK20-positive duct-like Cells. Due to the kinetics of these phenotypic changes, however, it has not been possible to demonstrate transitional stages of differentiation, which would express both markers at the same time. We took advantage of the fact that dexamethasone treatment inhibits the loss of amylase from acinar Cells to demonstrate transitional Cells co-expressing amylase and CK20. This was found both in vivo, where duct-ligation induced metaplasia, and in vitro, after isolation of acini. In addition, we found evidence for an acinar-to-islet conversion under the form of transitional Cells co-expressing amylase and insulin. These observations strengthen the notion that fully differentiated Cells, such as Exocrine pancreatic Cells, retain the capacity to undergo important phenotypic switches. This finding could have applications in tissue engineering or Cell replacement strategies.
Andrew B Leiter - One of the best experts on this subject based on the ideXlab platform.
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reduced neurog3 gene dosage shifts enteroendocrine progenitor towards goblet Cell lineage in the mouse intestine
Cellular and molecular gastroenterology and hepatology, 2021Co-Authors: Subir K Ray, Alper Kucukural, Gerard Gradwohl, Andrew B LeiterAbstract:Background & Aims Transient expression of Neurog3 commits intestinal secretory progenitors to become enteroendocrine-biased progenitors and hence drive enteroendocrine differentiation. Loss of Neurog3 in mouse resulted in the depletion of intestinal enteroendocrine Cells (EECs) and an increase in goblet Cells. Earlier studies in developing mouse pancreas identified a role of Neurog3 gene dosage in endocrine and Exocrine Cell fate allocation. We aimed to determine whether Neurog3 gene dosage controls fate choice of enteroendocrine progenitors. Methods We acquired mutant Neurog3 reporter mice carrying 2, 1, or null Neurog3 alleles to study Neurog3 gene dosage effect by lineage tracing. Cell types arising from Neurog3+ progenitors were determined by immunohistochemistry using antibodies against intestinal lineage-specific markers. RNA sequencing of sorted Neurog3+/+, Neurog3+/-, or bulk intestinal Cells were performed and differentially expressed genes were analyzed. Results We identified 2731 genes enriched in sorted Neurog3+/+-derived Cells in the Neurog3+/+EYFP mouse intestine when compared with bulk duodenum epithelial Cells. In the intestine of Neurog3+/-EGFP heterozygous mouse, we observed a 63% decrease in EEC numbers. Many Neurog3-derived Cells stained for goblet marker Mucin 2. RNA sequencing of sorted Neurog3+/- Cells uncovered enriched expression of genes characteristic for both goblet and enteroendocrine Cells, indicating the mixed lineages arose from Neurog3+ progenitors. Consistent with this hypothesis, deletion of both Neurog3 alleles resulted in the total absence of EECs. All Neurog3+-derived Cells stained for Mucin 2. Conclusions We identified that the fate of Neurog3+ enteroendocrine progenitors is dependent on Neurog3 gene dosage. High Neurog3 gene dosage enforces the commitment of secretory progenitors to an EE lineage, while constraining their goblet Cell lineage potential. Transcriptome profiling data was deposited to Gene Ontology omnibus, accession number: GSE149203 .
Gordon W Laurie - One of the best experts on this subject based on the ideXlab platform.
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heparanase deglycanation of syndecan 1 is required for binding of the epithelial restricted prosecretory mitogen lacritin
Journal of Cell Biology, 2006Co-Authors: Shannon L Beck, Ronald W Raab, Robert L Mckown, George L Coffman, Atsushi Utani, William J Chirico, Alan C Rapraeger, Gordon W LaurieAbstract:Cell surface heparan sulfate (HS) proteoglycans are carbohydrate-rich regulators of Cell migratory, mitogenic, secretory, and inflammatory activity that bind and present soluble heparin-binding growth factors (e.g., fibroblast growth factor, Wnt, Hh, transforming growth factor beta, amphiregulin, and hepatocyte growth factor) to their respective signaling receptors. We demonstrate that the deglycanated core protein of syndecan-1 (SDC1) and not HS chains nor SDC2 or -4, appears to target the epithelial selective prosecretory mitogen lacritin. An important and novel step in this mechanism is that binding necessitates prior partial or complete removal of HS chains by endogenous heparanase. This limits lacritin activity to sites where heparanase appears to predominate, such as sites of Exocrine Cell migration, secretion, renewal, and inflammation. Binding is mutually specified by lacritin's C-terminal mitogenic domain and SDC1's N terminus. Heparanase modification of the latter transforms a widely expressed HS proteoglycan into a highly selective surface-binding protein. This novel example of Cell specification through extraCellular modification of an HS proteoglycan has broad implications in development, homeostasis, and disease.
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heparanase deglycanation of syndecan 1 is required for binding of the epithelial restricted prosecretory mitogen lacritin
Journal of Cell Biology, 2006Co-Authors: Shannon L Beck, Ronald W Raab, Robert L Mckown, George L Coffman, Atsushi Utani, William J Chirico, Alan C Rapraeger, Gordon W LaurieAbstract:Cell surface heparan sulfate (HS) proteoglycans are carbohydrate-rich regulators of Cell migratory, mitogenic, secretory, and inflammatory activity that bind and present soluble heparin-binding growth factors (e.g., fibroblast growth factor, Wnt, Hh, transforming growth factor β, amphiregulin, and hepatocyte growth factor) to their respective signaling receptors. We demonstrate that the deglycanated core protein of syndecan-1 (SDC1) and not HS chains nor SDC2 or -4, appears to target the epithelial selective prosecretory mitogen lacritin. An important and novel step in this mechanism is that binding necessitates prior partial or complete removal of HS chains by endogenous heparanase. This limits lacritin activity to sites where heparanase appears to predominate, such as sites of Exocrine Cell migration, secretion, renewal, and inflammation. Binding is mutually specified by lacritin's C-terminal mitogenic domain and SDC1's N terminus. Heparanase modification of the latter transforms a widely expressed HS proteoglycan into a highly selective surface-binding protein. This novel example of Cell specification through extraCellular modification of an HS proteoglycan has broad implications in development, homeostasis, and disease.
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bm180 a novel basement membrane protein with a role in stimulus secretion coupling by lacrimal acinar Cells
American Journal of Physiology-cell Physiology, 1996Co-Authors: Gordon W Laurie, J D Glass, Rebecca A Ogle, C M Stone, J R Sluss, Lanlin ChenAbstract:Regulated secretion requires the developmental coupling of neuronal or hormonal stimuli to an exocytotic response, a multistep pathway whose appearance may be linked with Cellular adhesion to the newly formed Exocrine Cell basement membrane. We screened for adhesion-associated coupling activity using lacrimal acinar Cells and have identified “BM180”, a novel basement membrane protein enriched in guanidine HCl extracts of lacrimal and parotid Exocrine secretory glands. BM180 resides primarily in a previously inexamined lower molecular-mass basement membrane peak (peak 2) that contains Cell adhesion activity inhibitable with the anti-BM180 monoclonal antibody 3E12. Removal of peak 2 by gel filtration or preincubation of basement membrane with 3E12 decreased regulated peroxidase secretion by one-half without affecting constitutive secretion or the amount of Cellular peroxidase available for release. Adding back peak 2 restored regulated secretion in a dose-dependent and 3E12-inhibitable manner and suggested ...
Christopher V.e. Wright - One of the best experts on this subject based on the ideXlab platform.
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neurog3 gene dosage regulates allocation of endocrine and Exocrine Cell fates in the developing mouse pancreas
Developmental Biology, 2010Co-Authors: Sui Wang, Jingbo Yan, Daniel A Anderson, Maneesh C Kanal, Zheng Cao, Christopher V.e. WrightAbstract:Abstract The basic helix–loop–helix transcription factor Neurog3 (Neurogenin3 or Ngn3) actively drives endodermal progenitor Cells towards endocrine islet Cell differentiation during embryogenesis. Here, we manipulate Neurog3 expression levels in endocrine progenitor Cells without altering its expression pattern using heterozygosity and a hypomorph. Lowered Neurog3 gene dosage in the developing pancreatic epithelium reduces the overall production of endocrine islet Cells without significantly affecting the proportions of various islet Cell types that do form. A reduced Neurog3 production level in the endocrine-directed pancreatic progenitor population activates the expression of Neurog3 in an increased number of epithelial progenitors. Yet a significant number of these Neurog3+ Cells detected in heterozygous and hypomorphic pancreata, possibly those that express low levels of Neurog3, move on to adopt pancreatic ductal or acinar fates. These data directly demonstrate that achieving high levels of Neurog3 expression is a critical step for endocrine commitment from multipotent pancreatic progenitors. These findings also suggest that a high level of Neurog3 expression could mediate lateral inhibition or other unknown feedback mechanisms to regulate the number of Cells that initiate Neurog3 transcription and protein production. The control of Neurog3+ Cell number and the Neurog3 threshold-dependent endocrine differentiation mechanism combine to select a specific proportion of pancreatic progenitor Cells to adopt the islet Cell fate.
Subir K Ray - One of the best experts on this subject based on the ideXlab platform.
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reduced neurog3 gene dosage shifts enteroendocrine progenitor towards goblet Cell lineage in the mouse intestine
Cellular and molecular gastroenterology and hepatology, 2021Co-Authors: Subir K Ray, Alper Kucukural, Gerard Gradwohl, Andrew B LeiterAbstract:Background & Aims Transient expression of Neurog3 commits intestinal secretory progenitors to become enteroendocrine-biased progenitors and hence drive enteroendocrine differentiation. Loss of Neurog3 in mouse resulted in the depletion of intestinal enteroendocrine Cells (EECs) and an increase in goblet Cells. Earlier studies in developing mouse pancreas identified a role of Neurog3 gene dosage in endocrine and Exocrine Cell fate allocation. We aimed to determine whether Neurog3 gene dosage controls fate choice of enteroendocrine progenitors. Methods We acquired mutant Neurog3 reporter mice carrying 2, 1, or null Neurog3 alleles to study Neurog3 gene dosage effect by lineage tracing. Cell types arising from Neurog3+ progenitors were determined by immunohistochemistry using antibodies against intestinal lineage-specific markers. RNA sequencing of sorted Neurog3+/+, Neurog3+/-, or bulk intestinal Cells were performed and differentially expressed genes were analyzed. Results We identified 2731 genes enriched in sorted Neurog3+/+-derived Cells in the Neurog3+/+EYFP mouse intestine when compared with bulk duodenum epithelial Cells. In the intestine of Neurog3+/-EGFP heterozygous mouse, we observed a 63% decrease in EEC numbers. Many Neurog3-derived Cells stained for goblet marker Mucin 2. RNA sequencing of sorted Neurog3+/- Cells uncovered enriched expression of genes characteristic for both goblet and enteroendocrine Cells, indicating the mixed lineages arose from Neurog3+ progenitors. Consistent with this hypothesis, deletion of both Neurog3 alleles resulted in the total absence of EECs. All Neurog3+-derived Cells stained for Mucin 2. Conclusions We identified that the fate of Neurog3+ enteroendocrine progenitors is dependent on Neurog3 gene dosage. High Neurog3 gene dosage enforces the commitment of secretory progenitors to an EE lineage, while constraining their goblet Cell lineage potential. Transcriptome profiling data was deposited to Gene Ontology omnibus, accession number: GSE149203 .