Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA317661 | ENA |
REPOSITORIES: ENA
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Project description:Lgr5 marks adult stem cells in multiple adult organs and is a receptor for the Wnt-agonistic R-spondins (RSPOs). Intestinal, stomach and liver Lgr5+ stem cells grow in 3D cultures to form ever-expanding organoids, which resemble the tissues of origin. Wnt signaling is inactive and Lgr5 is not expressed under physiological conditions in the adult pancreas. However, we now report that the Wnt pathway is robustly activated upon injury by Partial Duct Ligation (PDL), concomitant with the appearance of Lgr5 expression in regenerating pancreatic ducts. In vitro, duct fragments from mouse pancreas initiate Lgr5 expression in RSPO1-based cultures, and develop into budding cyst-like structures (organoids) which expand 5-fold weekly for >40 weeks. Single isolated duct cells can also be cultured into pancreatic organoids, containing Lgr5 stem/progenitor cells that can be clonally expanded. Clonal pancreas organoids can be induced to differentiate into duct as well as endocrine cells upon transplantation, thus proving their bi-potentiality We generated arrays from whole pancreas, islet, acinar and duct (Sox9+ sorted) cells and pancreas derived cultures maintained in our defined medium. For the clustering analysis we substracted the pancreas array to all arrays. Genes 2 fold differentially expressed in the ductal array were used for the analsyis. For the genes enriched in organoid cultures compared to pancreas we substracted the organoid culture arrays to the pancreas array. Genes >2-fold differentially expressed were used for the analysis.
2013-09-17 | E-GEOD-50103 | biostudies-arrayexpress
Project description:The tissue dynamics that govern maintenance and regeneration of the pancreas remain largely unknown. In particular, the presence and nature of a cellular hierarchy remains a topic of debate. Previous lineage tracing strategies in the pancreas relied on specific marker genes for clonal labeling, which left other populations untested and failed to account for potential widespread phenotypical plasticity. Here we employed a tracing system that depends on replication-induced clonal marks. We found that in homeostasis, steady acinar replacement events characterize tissue dynamics, to which all acinar cells have an equal ability to contribute. Similarly, regeneration following pancreatitis was best characterized by an acinar self-replication model, as no evidence for a cellular hierarchy was detected. In particular, rapid regeneration in the pancreas was found to be driven by an accelerated rate of acinar fission-like events. Together these results provide a comprehensive and quantitative model of cell dynamics in the exocrine pancreas.
2021-08-05 | GSE171731 | GEO
Project description:Pancreas volume or mass varies more than 3-fold among adult humans. The heterogeneity is likely the result of genetics, diseases, and nutrition. Dietary protein intake and blood amino acid levels are known to affect pancreas mass, but the underlying mechanism is not well understood. The goal of this study is to determine how increased blood amino acid level (hyperaminoacidemia) induces pancreas expansion.Multiple complementary mouse and zebrafish models were used to study the impact of hyperaminoacidemia on pancreatic mass, acinar cell size and proliferation. Blood amino acid levels were manipulated by dietary protein content, or by pharmacologic or genetic interruption of glucagon signaling (IGS). The activation of mammalian target of rapamycin complex 1 (mTORC1) and Yes-associated protein 1 (YAP) were determined by pS6 and YAP staining. Sirolimus administration in mice and knockdown of solute carrier family 38 member 5b (slc38a5b) and yap/taz in zebrafish were used to determine the role of mTORC1, SLC38A5 and YAP/TAZ in acinar cell proliferation and pancreas expansion. We found that the IGS-induced pancreas expansion was the result of acinar cell proliferation and hypertrophy. Hyperaminoacidemia was the likely mediator as pancreas expansion was blunted by a low protein diet in mice and by knocking down the most highly expressed amino acid transporter gene, slc38a5b, in zebrafish lacking both glucagon receptor genes (gcgr-/-). In GCGR-Ab treated mice, inhibition of mTORC1 attenuated both hyperplasia and hypertrophy of acinar cells. There was a gene expression signature of YAP activation in acinar cells, consistent with increased YAP-expressing acinar cells in GCGR-Ab treated mice and increased fraction of acinar cells with nuclear YAP1 in gcgr-/- zebrafish. Knocking down yap1 or taz decreased mTORC1 activity and acinar cell hyperplasia and hypertrophy in gcgr-/- zebrafish. Hyperaminoacidemia leads to acinar cell proliferation and hypertrophy via activation of both mTORC1 and YAP pathways. The study discovered a previously unrecognized role of the YAP/Taz pathway in hyperaminoacidemia-induced acinar cell hypertrophy and hyperplasia.
2024-03-30 | GSE243695 | GEO
Project description:To investigate the role of the E3 ubiquitin ligase Thyroid Receptor Interacting Protein 12 (TRIP12) in pancreatic acinar cell identity and pancreatic carcinogenesis, we used genetically engineered mouse models of pancreas-selective Trip12 deletion, mutant Kras (G12D) and mutant P53 (R172H). We performed gene expression analysis using RNA-seq data from adult acinar cells. We established cell lines from murine pancreatic tumors.
2024-04-19 | GSE221587 | GEO
Project description:Serine protease inhibitor Kazal type 3 (Spink3) is a trypsin inhibitor in the pancreas. Spink3-/- pancreatic acinar cells are dead with excessive autophagy at birth (p0.5). To prove the role of nonapoptotic cell death with autophagy, we generated by transgenic technology the pancreas of Spink3-/-;XKI/+ mice contained both normal and dying acinar cells with autophagy. In this new mouse model, chronic inflammation occurred in the pancreas, indicating that some signals from nonapoptotic dead cell induce chronic inflammation in the pancreas. All samples were the pancreas at p0.5. Sample 1 and 2 are the pancreas from wild type (Spink3+/+, control) mice. Sample 3 and 4 are the pancreas from Spink3-/-, which all pancreatic acinar cells show induced nonapoptotic cell death with autophagy. Sample 5 and 6 are the pancreas from Spink3-/-XKI/+, about half acinar cells are normal, but other acinar cells show induced nonapoptotic cell death with autophagy.
2016-07-16 | E-GEOD-48946 | biostudies-arrayexpress
Project description:Single cell-based studies have revealed tremendous cellular heterogeneity in stem cell and progenitor compartments, suggesting continuous differentiation trajectories with intermixing of cells at various states of lineage commitment and notable degree of plasticity during organogenesis. The hepato-pancreato-biliary organ system relies on a small endoderm progenitor compartment that gives rise to a variety of different adult tissues, including liver, pancreas, gallbladder, and extra-hepatic bile ducts. Experimental manipulation of various developmental signals in the mouse embryo underscored important cellular plasticity in this embryonic territory. This is also reflected in the existence of human genetic syndromes as well as congenital or environmentally-caused human malformations featuring multiorgan phenotypes in liver, pancreas and gallbladder. Nevertheless, the precise lineage hierarchy and succession of events leading to the segregation of an endoderm progenitor compartment into hepatic, biliary, and pancreatic structures are not yet established. Here, we combine computational modelling approaches with genetic lineage tracing to assess the tissue dynamics accompanying the ontogeny of the hepato-pancreato-biliary organ system. We show that a multipotent progenitor domain persists at the border between liver and pancreas, even after pancreatic fate is specified, contributing to the formation of several organ derivatives, including the liver. Moreover, using single-cell RNA sequencing we define a specialized niche that possibly supports such extended cell fate plasticity.
2021-07-01 | MODEL2105030001 | BioModels
Project description:BACKGROUND & AIMS: Acinar cells produce digestive enzymes that impede transcriptomic characterization of the exocrine pancreas. Thus, single-cell RNA-sequencing (scRNA-seq) studies of the pancreas underrepresent acinar cells relative to histological expectations, and a robust approach to capture pancreatic cell responses in disease states is needed. We sought to innovate a method that overcomes these challenges to accelerate study of the pancreas in health and disease. METHODS: We introduce FixNCut, a scRNA-seq approach where tissue is reversibly fixed with dithiobis(succinimidyl propionate) prior to dissociation and single-cell preparation. We apply FixNCut to an established mouse model of acute pancreatitis, validate findings using GeoMx whole transcriptome atlas (WTA) profiling, and integrate our data with prior studies to benchmark our method in both mouse and human pancreas datasets. RESULTS: FixNCut achieves unprecedented definition of challenging pancreatic cells including acinar and immune populations in homeostasis and acute pancreatitis, and identifies changes in all major cell types during injury and recovery. We define the acinar transcriptome during homeostasis and acinar-to-ductal metaplasia and establish a unique gene set to measure deviation from normal acinar identity. We characterize pancreatic immune cells, and analysis of T-cell subsets reveals a polarization of the homeostatic pancreas towards type-2 immunity. We report immune responses during acute pancreatitis and recovery, including early neutrophil infiltration, expansion of dendritic cell subsets, and a substantial shift in the transcriptome of macrophages due to both resident macrophage activation and monocyte infiltration. CONCLUSIONS: FixNCut preserves pancreatic transcriptomes to uncover novel cell states during homeostasis and following pancreatitis, establishing a broadly applicable approach and reference atlas for study of pancreas biology and disease.
2024-02-28 | GSE235874 | GEO
Project description:Intracellular trafficking is essential for proper cell signaling. In the pancreas, secretory cells rely on trafficking to regulate blood glucose and digestion. Pancreatic disorders reflect defects in function or development, evoking considerable interest in understanding the molecular genetics governing pancreatic organogenesis. Here, we show the transcription factor NFIA regulates trafficking in both the embryonic and adult pancreas, affecting both developmental cell fate decisions and adult physiology. NFIA deletion from pancreatic progenitors led to the development of more acinar cells and ducts and fewer endocrine cells, whereas ectopic NFIA promoted endocrine formation. We found that NFIA’s effects on trafficking influence endocrine/exocrine cell fate decisions through regulation of Notch. Adult NFIA-deficient mice develop diabetic phenotypes due to impaired insulin granule trafficking and defects in acinar zymogen secretion. This study shows how a single transcription factor, NFIA, thus exerts profound effects on both embryonic cell fate and adult physiology by regulating vesicle trafficking.
2017-09-14 | GSE86909 | GEO
Project description:Cellular identity during development is under the control of transcription factors that form gene regulatory networks. However, the transcription factors and gene regulatory networks underlying cellular identity in the human adult pancreas remain largely unexplored. Here, we integrate multiple single-cell RNA-sequencing datasets of the human adult pancreas, totaling 7393 cells, and comprehensively reconstruct gene regulatory networks. We show that a network of 142 transcription factors forms distinct regulatory modules that characterize pancreatic cell types. We present evidence that our approach identifies key regulators of cell identity in the human adult pancreas. We predict that HEYL, BHLHE41 and JUND are active in acinar, beta and alpha cells, respectively, and show that these proteins are present in the human adult pancreas as well as in human induced pluripotent stem cell (hiPSC)-derived islet cells. Using single cell transcriptomics, we found that JUND represses beta cell genes in hiPSC-alpha cells. Both BHLHE41 and JUND depletion seemed to increase the number of sc-enterochromaffin cells in hiPSC-derived islets. The comprehensive gene regulatory network atlas can be explored interactively online. We anticipate our analysis to be the starting point for a more sophisticated dissection of how transcription factors regulate cell identity in the human adult pancreas. Furthermore, given that transcription factors are major regulators of embryo development and are often perturbed in diseases, a comprehensive understanding of how transcription factors work will be relevant in development and disease.
2020-09-23 | GSE156490 | GEO