scholarly journals The Wnt signaling receptor Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets

2021 ◽  
Vol 4 (5) ◽  
pp. e201900490
Author(s):  
Mariano F Zacarías-Fluck ◽  
Toni Jauset ◽  
Sandra Martínez-Martín ◽  
Jastrinjan Kaur ◽  
Sílvia Casacuberta-Serra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Wnt Signaling ◽  
Pancreatic Islets ◽  
Global Gene Expression ◽  
Β Cell ◽  
Cell Dedifferentiation ◽  
Physiological Structure ◽  
Transcriptional Target

The huge cadre of genes regulated by Myc has obstructed the identification of critical effectors that are essential for Myc-driven tumorigenesis. Here, we describe how only the lack of the receptor Fzd9, previously identified as a Myc transcriptional target, impairs sustained tumor expansion and β-cell dedifferentiation in a mouse model of Myc-driven insulinoma, allows pancreatic islets to maintain their physiological structure and affects Myc-related global gene expression. Importantly, Wnt signaling inhibition in Fzd9-competent mice largely recapitulates the suppression of proliferation caused by Fzd9 deficiency upon Myc activation. Together, our results indicate that the Wnt signaling receptor Fzd9 is essential for Myc-induced tumorigenesis in pancreatic islets.

scholarly journals The effects of high glucose exposure on global gene expression and DNA methylation in human pancreatic islets

2018 ◽  
Vol 472 ◽  
pp. 57-67 ◽  
Author(s):  
Elin Hall ◽  
Marloes Dekker Nitert ◽  
Petr Volkov ◽  
Siri Malmgren ◽  
Hindrik Mulder ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Pancreatic Islets ◽  
High Glucose ◽  
Global Gene Expression ◽  
Human Pancreatic Islets ◽  
Glucose Exposure

scholarly journals Differentiation of Sendai Virus-Reprogrammed iPSC into β Cells, Compared with Human Pancreatic Islets and Immortalized β Cell Line

2018 ◽  
Vol 27 (10) ◽  
pp. 1548-1560 ◽  
Author(s):  
Silvia Pellegrini ◽  
Fabio Manenti ◽  
Raniero Chimienti ◽  
Rita Nano ◽  
Linda Ottoboni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Islets ◽  
Cell Line ◽  
Expression Profile ◽  
Sendai Virus ◽  
Secretory Function ◽  
Β Cells ◽  
Β Cell ◽  
Insulin Producing Cells ◽  
Gene And Protein Expression

Background: New sources of insulin-secreting cells are strongly in demand for treatment of diabetes. Induced pluripotent stem cells (iPSCs) have the potential to generate insulin-producing cells (iβ). However, the gene expression profile and secretory function of iβ still need to be validated in comparison with native β cells. Methods: Two clones of human iPSCs, reprogrammed from adult fibroblasts through integration-free Sendai virus, were differentiated into iβ and compared with donor pancreatic islets and EndoC-βH1, an immortalized human β cell line. Results: Both clones of iPSCs differentiated into insulin+ cells with high efficiency (up to 20%). iβ were negative for pluripotency markers (Oct4, Sox2, Ssea4) and positive for Pdx1, Nkx6.1, Chromogranin A, PC1/3, insulin, glucagon and somatostatin. iβ basally secreted C-peptide, glucagon and ghrelin and released insulin in response either to increasing concentration of glucose or a depolarizing stimulus. The comparison revealed that iβ are remarkably similar to donor derived islets in terms of gene and protein expression profile and similar level of heterogeneity. The ability of iβ to respond to glucose instead was more related to that of EndoC-βH1. Discussion: We demonstrated that insulin-producing cells generated from iPSCs recapitulate fundamental gene expression profiles and secretory function of native human β cells.

scholarly journals Temporal Transcriptome Analysis Reveals Dynamic Gene Expression Patterns Driving β-Cell Maturation

2021 ◽  
Vol 9 ◽  
Author(s):  
Tiziana Sanavia ◽  
Chen Huang ◽  
Elisabetta Manduchi ◽  
Yanwen Xu ◽  
Prasanna K. Dadi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Calcium Influx ◽  
Expression Patterns ◽  
Embryonic Stem ◽  
Global Gene Expression ◽  
Cell Maturation ◽  
Β Cells ◽  
Β Cell ◽  
Granule Formation

Newly differentiated pancreatic β cells lack proper insulin secretion profiles of mature functional β cells. The global gene expression differences between paired immature and mature β cells have been studied, but the dynamics of transcriptional events, correlating with temporal development of glucose-stimulated insulin secretion (GSIS), remain to be fully defined. This aspect is important to identify which genes and pathways are necessary for β-cell development or for maturation, as defective insulin secretion is linked with diseases such as diabetes. In this study, we assayed through RNA sequencing the global gene expression across six β-cell developmental stages in mice, spanning from β-cell progenitor to mature β cells. A computational pipeline then selected genes differentially expressed with respect to progenitors and clustered them into groups with distinct temporal patterns associated with biological functions and pathways. These patterns were finally correlated with experimental GSIS, calcium influx, and insulin granule formation data. Gene expression temporal profiling revealed the timing of important biological processes across β-cell maturation, such as the deregulation of β-cell developmental pathways and the activation of molecular machineries for vesicle biosynthesis and transport, signal transduction of transmembrane receptors, and glucose-induced Ca2+ influx, which were established over a week before β-cell maturation completes. In particular, β cells developed robust insulin secretion at high glucose several days after birth, coincident with the establishment of glucose-induced calcium influx. Yet the neonatal β cells displayed high basal insulin secretion, which decreased to the low levels found in mature β cells only a week later. Different genes associated with calcium-mediated processes, whose alterations are linked with insulin resistance and deregulation of glucose homeostasis, showed increased expression across β-cell stages, in accordance with the temporal acquisition of proper GSIS. Our temporal gene expression pattern analysis provided a comprehensive database of the underlying molecular components and biological mechanisms driving β-cell maturation at different temporal stages, which are fundamental for better control of the in vitro production of functional β cells from human embryonic stem/induced pluripotent cell for transplantation-based type 1 diabetes therapy.

scholarly journals Regulation of pancreatic islet gene expression in mouse islets by pregnancy

2010 ◽  
Vol 207 (3) ◽  
pp. 265-279 ◽  
Author(s):  
B T Layden ◽  
V Durai ◽  
M V Newman ◽  
A M Marinelarena ◽  
C W Ahn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Function ◽  
Global Gene Expression ◽  
Surfactant Protein ◽  
Surfactant Protein D ◽  
Mrna Levels ◽  
Β Cell ◽  
Expression Array ◽  
Follow Up Studies

Pancreatic β cells adapt to pregnancy-induced insulin resistance by unclear mechanisms. This study sought to identify genes involved in β cell adaptation during pregnancy. To examine changes in global RNA expression during pregnancy, murine islets were isolated at a time point of increased β cell proliferation (E13.5), and RNA levels were determined by two different assays (global gene expression array and G-protein-coupled receptor (GPCR) array). Follow-up studies confirmed the findings for select genes. Differential expression of 110 genes was identified and follow-up studies confirmed the changes in select genes at both the RNA and protein level. Surfactant protein D (SP-D) mRNA and protein levels exhibited large increases, which were confirmed in murine islets. Cytokine-induced expression of SP-D in islets was also demonstrated, suggesting a possible role as an anti-inflammatory molecule. Complementing these studies, an expression array was performed to define pregnancy-induced changes in expression of GPCRs that are known to impact islet cell function and proliferation. This assay, the results of which were confirmed using real-time reverse transcription-PCR assays, demonstrated that free fatty acid receptor 2 and cholecystokinin receptor A mRNA levels were increased at E13.5. This study has identified multiple novel targets that may be important for the adaptation of islets to pregnancy.

scholarly journals Phenotypic and global gene expression profile changes between low passage and high passage MIN-6 cells

2006 ◽  
Vol 191 (3) ◽  
pp. 665-676 ◽  
Author(s):  
Lorraine O’Driscoll ◽  
Patrick Gammell ◽  
Eadaoin McKiernan ◽  
Eoin Ryan ◽  
Per Bendix Jeppesen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alkaline Phosphatase ◽  
Global Gene Expression ◽  
Stem Cell Marker ◽  
Β Cell ◽  
High Passage ◽  
Long Term Culture ◽  
Low Passage

The long-term potential to routinely use replacement β cells/islets as cell therapy for type 1 diabetes relies on our ability to culture such cells/islets, in vitro, while maintaining their functional status. Previous β cell studies, by ourselves and other researchers, have indicated that the glucose-stimulated insulin secretion (GSIS) phenotype is relatively unstable, in long-term culture. This study aimed to investigate phenotypic and gene expression changes associated with this loss of GSIS, using the MIN-6 cell line as model. Phenotypic differences between MIN-6(L, low passage) and MIN-6(H, high passage) were determined by ELISA (assessing GSIS and cellular (pro)insulin content), proliferation assays, phase contrast light microscopy and analysis of alkaline phosphatase expression. Differential mRNA expression was investigated using microarray, bioinformatics and real-time PCR technologies. Long-term culture was found to be associated with many phenotypic changes, including changes in growth rate and cellular morphology, as well as loss of GSIS. Microarray analyses indicate expression of many mRNAs, including many involved in regulated secretion, adhesion and proliferation, to be significantly affected by passaging/ long-term culture. Loss/reduced levels, in high passage cells, of certain transcripts associated with the mature β cell, together with increased levels of neuron/glia-associated mRNAs, suggest that, with time in culture, MIN-6 cells may revert to an early (possibly multi-potential), poorly differentiated, ‘precursor-like’ cell type. This observation is supported by increased expression of the stem cell marker, alkaline phosphatase.

scholarly journals Diet-induced gene expression of isolated pancreatic islets from a polygenic mouse model of the metabolic syndrome

Diabetologia ◽  
2009 ◽  
Vol 53 (2) ◽  
pp. 309-320 ◽  
Author(s):  
T. Dreja ◽  
Z. Jovanovic ◽  
A. Rasche ◽  
R. Kluge ◽  
R. Herwig ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Syndrome ◽  
Mouse Model ◽  
Pancreatic Islets ◽  
Isolated Pancreatic Islets ◽  
The Metabolic Syndrome
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