Genome-wide mRNA profiling of adult human pancreatic beta and duct cells in comparison to other human tissues
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE30803 | GEO | 2011/07/21
SECONDARY ACCESSION(S): PRJNA144453
REPOSITORIES: GEO
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Project description:Aims: establishment of reference samples to investigate gene expression selective for endocrine or ductal-exocrine cells within the adult human pancreas. To this end, human islet endocrine cells, FACS-enriched in insulin+ cells, (n=3) and human exocrine ductal cells (n=2) are compared on Affymetrix HG133A platform with duplicate hybridizations of a panel of other primary human tissues. The microarray analysis was performed on 3 pools of human beta cell-enriched cell fractions, isolated from 10 non-selected donor organs, and 2 pools of duct cell-enriched fractions obtained from 6 non-selected donor pancreases. The cells were suspension-cultured for 2-3 weeks along standard procedures and with no specific treatment prior to FACS-sorting and RNA extraction. The average composition of human beta cell-preparations was 55 ± 13% insulin+ cells, 13±8% glucagon+ cells and 21 ±7% non-granulated cells. Pancreatic duct cells-enriched preparations contained 85 ±7% cytokeratin 19+ cells with 4 ± 1% insulin+ cells and 6 ±4% glucagon+ cells and were isolated as described by Heimberg H. et al.( Diabetes 2001,49: 571-579 ). Pancreatic cell mRNA profiles were compared to those of a panel of other human primary tissues (n=2 biological replicates). This dataset is part of the TransQST collection.
2011-07-21 | E-GEOD-30803 | biostudies-arrayexpress
Project description:The exocrine compartment of the pancreas consisting of ducts and acini makes up most of the pancreatic tissue and is the site of origin for pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Our understanding of the initiation and progression of human PDAC is limited because of challenges associated with maintaining acinar cells in culture. Here we report the commitment of human pluripotent stem cells towards pancreatic duct-like and acini-like organoids that express properties of the neonatal exocrine pancreas. The expression of PDAC-oncogenes KRasG12D or GNASR201C induced cell lineage-specific effects where GNASR201C was more effective in ductal compared to acinar organoids. KRasG12D was more effective in modeling cancer in vivo when expressed in acinar cells and was associated with acinar to ductal metaplastic changes in culture and in vivo. Thus we demonstrate lineage tropism and plasticity in the human exocrine pancreas and identify a renewable source of ductal and acinar epithelia for understanding exocrine development and diseases.
2021-04-16 | GSE169008 | GEO
Project description:Pancreatic acinar cells can dedifferentiate upon tissue injury and acquire ductal characteristics. This acquisition of duct cell features is critical in tumor development. Nevertheless, duct cells themselves are less prone for development of PDAC (pancreatic ductal adenocarcinoma) than dedifferentiated acini. We aimed to clarify which genes are unique for dedifferentiated acini. Mixed exocrine preparations of acinar and duct cells were obtained from human pancreatic donor organs and cultured to induce dedifferentiation. We lineage-labeled and FACS-purified these human dedifferentiated acinar cells and compared them to duct cells from the same donor (n=5).
2021-06-17 | E-MTAB-9386 | biostudies-arrayexpress
Project description:Aims/hypothesis: Duct cells isolated from adult human pancreas can be reprogrammed to express islet beta cell genes by adenoviral transduction of the developmental transcription factor neurogenin3 (Ngn3). In this study we aimed to fully characterize the extent of this reprogramming and intended to improve it. Methods: The extent of the Ngn3-mediated duct-to-endocrine cell reprogramming was measured employing genome wide mRNA profiling. By modulation of the Delta-Notch signaling or addition of pancreatic endocrine transcription factors Myt1, MafA and Pdx1 we intended to improve the reprogramming. Results: Ngn3 stimulates duct cells to express a focused set of genes that are abundant in islet endocrine cells and/or neural tissues. This neuro-endocrine shift, however, covers a minor fraction (5%) of the estimated genome-wide transcriptome difference between duct and islet endocrine cells. Interestingly, transduction of exogenous Ngn3 activates endogenous Ngn3 suggesting auto-activation of this gene. Furthermore, pancreatic endocrine reprogramming of human duct cells can be moderately enhanced by inhibition of Delta-Notch signaling as well as by co-expressing the transcription factor Myt1, but not MafA and Pdx1. Conclusions/interpretation: The results provide further insight into the plasticity of adult human duct cells and suggest measurable routes to enhance Ngn3-mediated in vitro reprogramming protocols for regenerative beta cell therapy in diabetes. We used Affymetrix HG133A and HG133B to get a comprehensive view on the reprogramming potential in vitro of human pancreatic duct cell cultures (n=3-4) at 3 and 14/20 days after ectopic adenoviral expression of murine neurogenin 3 as compared to GFP-expressing control vectors.
2012-07-11 | GSE30802 | GEO
Project description:Aims/hypothesis: Duct cells isolated from adult human pancreas can be reprogrammed to express islet beta cell genes by adenoviral transduction of the developmental transcription factor neurogenin3 (Ngn3). In this study we aimed to fully characterize the extent of this reprogramming and intended to improve it. Methods: The extent of the Ngn3-mediated duct-to-endocrine cell reprogramming was measured employing genome wide mRNA profiling. By modulation of the Delta-Notch signaling or addition of pancreatic endocrine transcription factors Myt1, MafA and Pdx1 we intended to improve the reprogramming. Results: Ngn3 stimulates duct cells to express a focused set of genes that are abundant in islet endocrine cells and/or neural tissues. This neuro-endocrine shift, however, covers a minor fraction (5%) of the estimated genome-wide transcriptome difference between duct and islet endocrine cells. Interestingly, transduction of exogenous Ngn3 activates endogenous Ngn3 suggesting auto-activation of this gene. Furthermore, pancreatic endocrine reprogramming of human duct cells can be moderately enhanced by inhibition of Delta-Notch signaling as well as by co-expressing the transcription factor Myt1, but not MafA and Pdx1. Conclusions/interpretation: The results provide further insight into the plasticity of adult human duct cells and suggest measurable routes to enhance Ngn3-mediated in vitro reprogramming protocols for regenerative beta cell therapy in diabetes. We used Affymetrix HG133A and HG133B to get a comprehensive view on the reprogramming potential in vitro of human pancreatic duct cell cultures (n=3-4) at 3 and 14/20 days after ectopic adenoviral expression of murine neurogenin 3 as compared to GFP-expressing control vectors. The microarray analysis was performed on 3 independent samples that each contained RNA extracted from a pool of 3 independent donor pancreata. The total number of non-selected donor organs is 9. Transcripts were considered as differentially regulated by Ngn3 when 1.5 fold (LCB, unpaired P < 0.05) up- or down-regulated in AdGFP-Ngn3 versus AdGFP controls, at 3 and/or 14 dpi. Transcripts that showed differential expression between day 3 and day 14 in AdGFP-Ngn3 duct cells but not in AdGFP control cells, were also considered Ngn3-regulated
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Project description:Stem and progenitor cells in the adult human pancreas provide an under-explored resource for regenerative medicine. Using micro-manipulation and methylcellulose-containing colony/organoid assays, we identified cells within the human cadaveric exocrine pancreas that fulfill the definition of a stem cell: able to self-renew and differentiate. Exocrine tissues were collected after the isolation of endocrine cells, dissociated into single cells, and plated into a 3-dimensional semisolid medium. We found that some pancreatic ductal cells gave rise to cystic colonies/organoids containing pancreatic duct, acinar, and endocrine lineage cells. These cells self-renewed and expanded approximately 300-fold over 9 weeks. When transplanted into diabetic mice, colonies/organoids lowered blood glucose levels and gave rise to insulin-expressing endocrine cells. Thus, stem/progenitor-like cells capable of self-renewal and differentiation either preexist in the adult human pancreas or readily adapt in culture. These human cells have implications for therapy in diabetes patients.
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Project description:During embryogenesis, exocrine and endocrine pancreatic tissues are formed in distinct regions within the branched ductal structure in mice. We previously reported that exocrine-specific inactivation of Pdx1, an indispensable gene for pancreatogenesis, by Elastase-Cre caused not only hypoplastic exocrine formation but also substantial endocrine defects resulting in diabetic phenotype, indicating the existence of exocrine-driven factor(s) that regulate proper endocrine development. We obtained pancreata from control and mutant mice at P1 and subjected to microarray analysis.
2019-02-13 | GSE118665 | GEO
Project description:The Ppy-gene encodes the pancreatic polypeptide (PP) secreted by PP- or - cells, an endocrine cell type located in the islet periphery. For a detailed characterization of PP cells, we aimed to establish PP cell lines. To this end, we generated Ppy-Cre;Rosa26-CAG-LSL-Large T mice, in which the SV40 large T antigen (TAg) is expressed in Ppy-expressing cells upon Cre-loxP-mediated recombination. Ppy-Cre;Rosa26-CAG-LSL-Large T mice, surprisingly, developed pancreatic ductal adenocarcinoma (PDAC) rapidly by 3 to 4 weeks of age, while mice with insulin2-Cre-mediated activation of TAg developed insulinomas. This suggests that PDACs could arise from the islet/endocrine cells, which is rather unexpected as PDACs are generally believed to originate from the pancreatic acinar or ductal cells. RNA-seq analysis of transformed Ppy-lineage cells in 7-day old islets showed downregulation of endocrine genes, upregulation of exocrine, ductal genes, and upregulation of PDAC-related genes and pathways, respectively. These results suggest that expression of an oncogene in Ppy-lineage cells leads to a fate switch in these endocrine precursors that causes them to adopt a PDAC cell fate. Our findings revealed that Ppy-lineage cells may be one of the origins of PDAC and provide novel insights into the heterogeneity in pathogenesis of pancreatic cancer and its personalized therapy.
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Project description:We used single-cell RNA-sequencing to generate transcriptional profiles of endocrine and exocrine cell types of the human pancreas. Pancreatic tissue and islets were obtained from six healthy and four T2D cadaveric donors. Islets were cultured and dissociated into single-cell suspension. Viable individual cells were distributed via fluorescence-activated cell sorted (FACS) into 384-well plates containing lysis buffer. Single-cell cDNA libraries were generated using the Smart-seq2 protocol. Gene expression was quantified as reads per kilobase transcript and per million mapped reads (RPKM) using rpkmforgenes. Bioinformatics analysis was used to classify cells into cell types without knowledge of cell types or prior purification of cell populations. We revealed subpopulations in endocrine and exocrine cell types, identified genes with interesting correlations to body mass index (BMI) in specific cell types and found transcriptional alterations in T2D. Complementary whole-islet RNA-seq data have also been deposited at ArrayExpress under accession number E-MTAB-5060 (http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-5060).
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