| 1. |
- Ameri, Jacqueline, et al.
(författare)
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FGF2 Specifies hESC-Derived Definitive Endoderm into Foregut/Midgut Cell Lineages in a Concentration-Dependent Manner.
- 2010
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 28, s. 45-56
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Tidskriftsartikel (refereegranskat)abstract
- Fibroblast growth factor (FGF) signaling controls axis formation during endoderm development. Studies in lower vertebrates have demonstrated that FGF2 primarily patterns the ventral foregut endoderm into liver and lung, whereas FGF4 exhibits broad anterior-posterior and left-right patterning activities. Furthermore, an inductive role of FGF2 during dorsal pancreas formation has been shown. However, whether FGF2 plays a similar role during human endoderm development remains unknown. Here, we show that FGF2 specifies hESC-derived definitive endoderm (DE) into different foregut lineages in a dosage-dependent manner. Specifically, increasing concentrations of FGF2 inhibits hepatocyte differentiation, whereas intermediate concentration of FGF2 promotes differentiation towards a pancreatic cell fate. At high FGF2 levels specification of midgut endoderm into small intestinal progenitors is increased at the expense of PDX1+ pancreatic progenitors. High FGF2 concentrations also promote differentiation towards an anterior foregut pulmonary cell fate. Finally, by dissecting the FGF receptor intracellular pathway that regulates pancreas specification, we demonstrate for the first time to our knowledge that induction of PDX1+ pancreatic progenitors relies on FGF2-mediated activation of the MAPK signaling pathway. Altogether, these observations suggest a broader gut endodermal patterning activity of FGF2 that corresponds to what has previously been advocated for FGF4, implying a functional switch from FGF4 to FGF2 during evolution. Thus, our results provide new knowledge of how cell fate specification of human DE is controlled - facts that will be of great value for future regenerative cell therapies.
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| 2. |
- Arregi, Igor, et al.
(författare)
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Retinol dehydrogenase-10 regulates pancreas organogenesis and endocrine cell differentiation via paracrine retinoic acid signaling
- 2016
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 157:12, s. 4615-4631
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin A-derived retinoic acid (RA) signals are critical for the development of several organs, including the pancreas. However, the tissue-specific control of RA synthesis in organ and cell lineage development has only poorly been addressed in vivo. Here, we show that retinol dehydrogenase-10 (Rdh10), a key enzyme in embryonic RA production, has important functions in pancreas organogenesis and endocrine cell differentiation. Rdh10 was expressed in the developing pancreas epithelium and surrounding mesenchyme. Rdh10 null mutant mouse embryos exhibited dorsal pancreas agenesis and a hypoplastic ventral pancreas with retarded tubulogenesis and branching. Conditional disruption of Rdh10 from the endoderm caused increased mortality, reduced body weight, and lowered blood glucose levels after birth. Endodermal Rdh10 deficiency led to a smaller dorsal pancreas with a reduced density of early glucagonβ and insulinβ cells. During the secondary transition, the reduction of Neurogenin3β endocrine progenitors in the mutant dorsal pancreas accounted for fewer β-and α-cells. Changes in the expression of β-and α-cellspecific transcription factors indicated that Rdh10 might also participate in the terminal differentiation of endocrine cells. Together, our results highlight the importance of both mesenchymal andepithelialRdh10forpancreogenesisandthefirstwaveofendocrinecell differentiation.Wefurther propose a model in which the Rdh10-expressing exocrine tissue acts as an essential source ofRAsignals in the second wave of endocrine cell differentiation.
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| 3. |
- Artner, Isabella, et al.
(författare)
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MafA and MafB Regulate Genes Critical to beta-Cells in a Unique Temporal Manner
- 2010
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 59:10, s. 2530-2539
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Several transcription factors are essential to pancreatic islet beta-cell development, proliferation, and activity, including MafA and MafB. However, MafA and MafB are distinct from others in regard to temporal and islet cell expression pattern, with beta-cells affected by MafB only during development and exclusively by MafA in the adult. Our aim was to define the functional relationship between these closely related activators to the beta-cell. RESEARCH DESIGN AND METHODS-The distribution of MafA and MafB in the beta-cell population was determined immunohistochemically at various developmental and perinatal stages in mice. To identify genes regulated by MafB, microarray profiling was performed on wild-type and MafB(-/-) pancreata at embryonic day 18.5, with candidates evaluated by quantitative RT-PCR and in situ hybridization. The potential role of MafA in the expression of verified targets was next analyzed in adult islets of a pancreas-wide MafA mutant (termed MafA(Delta Panc)). RESULTS-MafB was produced in a larger fraction of beta-cells than MafA during development and found to regulate potential effectors of glucose sensing, hormone processing, vesicle formation, and insulin secretion. Notably, expression from many of these genes was compromised in MafA(Delta Panc) islets, suggesting that MafA is required to sustain expression in adults. CONCLUSIONS-Our results provide insight into the sequential manner by which MafA and MafB regulate islet beta-cell formation and maturation. Diabetes 59:2530-2539, 2010
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| 4. |
- Artner, Isabella, et al.
(författare)
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MaFA is a dedicated activator of the insulin gene in vivo.
- 2008
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Ingår i: Journal of Endocrinology. - 1479-6805. ; May 30, s. 271-279
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Tidskriftsartikel (refereegranskat)abstract
- As successful generation of insulin producing cells could be used for diabetes treatment, a concerted effort is being made to understand the molecular programs underlying islet beta cell formation and function. The closely related MafA and MafB transcription factors are both key mammalian beta cell regulators. MafA and MafB are co-expressed in insulin+ beta cells during embryogenesis, while in the adult pancreas MafA is only produced in beta cells and MafB in glucagon+ alpha cells. MafB-/- animals are also deficient in insulin+ and glucagon+ cell production during embryogenesis. However, only MafA over-expression selectively induced endogenous Insulin mRNA production in cell line based assays, while MafB specifically promoted Glucagon expression. Here we analyzed if these factors were sufficient to induce insulin+ and/or glucagon+ cell formation within embryonic endoderm using the chick in ovo electroporation assay. Ectopic expression of MafA, but not MafB, promoted Insulin production, however neither MafA nor MafB were capable of inducing Glucagon. Co-electroporation of MafA with the Ngn3 transcription factor resulted in the development of more organized cell clusters containing both insulin and glucagon producing cells. Analysis of chimeric proteins of MafA and MafB demonstrated that chick Insulin activation depended on sequences within the MafA C-terminal DNA binding domain. MafA was also bound to Insulin and Glucagon transcriptional control sequences in mouse embryonic pancreas and beta cell lines. Collectively, these results demonstrate a unique ability for MafA to independently activate Insulin transcription.
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| 5. |
- Asplund, Olof, et al.
(författare)
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Islet Gene View-a tool to facilitate islet research
- 2022
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Ingår i: Life Science Alliance. - : Life Science Alliance, LLC. - 2575-1077. ; 5:12
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Tidskriftsartikel (refereegranskat)abstract
- Characterization of gene expression in pancreatic islets and its alteration in type 2 diabetes (T2D) are vital in understanding islet function and T2D pathogenesis. We leveraged RNA sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. Expression data were related to islet phenotypes, diabetes status, other islet-expressed genes, islet hormone-encoding genes and for expression in insulin target tissues. The IGW web application produces output graphs for a particular gene of interest. In IGW, 284 differentially expressed genes (DEGs) were identified in T2D donor islets compared with controls. Forty percent of DEGs showed cell-type enrichment and a large proportion significantly co-expressed with islet hormone-encoding genes; glucagon (GCG, 56%), amylin (IAPP, 52%), insulin (INS, 44%), and somatostatin (SST, 24%). Inhibition of two DEGs, UNC5D and SERPINE2, impaired glucose-stimulated insulin secretion and impacted cell survival in a human beta-cell model. The exploratory use of IGW could help designing more comprehensive functional follow-up studies and serve to identify therapeutic targets in T2D.
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| 6. |
- Bacos, Karl, et al.
(författare)
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Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets
- 2023
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Ingår i: The Journal of clinical investigation. - 0021-9738 .- 1558-8238. ; 133:4
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic β-cells. To identify candidates contributing to T2D pathophysiology, we studied human pancreatic islets from ~300 individuals. We found 395 differentially expressed genes (DEGs) in islets from individuals with T2D, including, to our knowledge, novel (OPRD1, PAX5, TET1) and previously identified (CHL1, GLRA1, IAPP) candidates. A third of the identified islet expression changes may predispose to diabetes, as they associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human β-cells based on single-cell RNA-sequencing data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D-SNPs. Mouse knock-out strains demonstrated that T2D-associated candidates regulate glucose homeostasis and body composition in vivo. Functional validation showed that mimicking T2D-associated changes for OPRD1, PAX5, and SLC2A2 impaired insulin secretion. Impairments in Pax5-overexpressing β-cells were due to severe mitochondrial dysfunction. Finally, we discovered PAX5 as a potential transcriptional regulator of many T2D-associated DEGs in human islets. Overall, we identified molecular alterations in human pancreatic islets contributing to β-cell dysfunction in T2D pathophysiology.
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| 7. |
- Bennet, Hedvig, et al.
(författare)
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Serotonin (5-HT) receptor 2b activation augments glucose-stimulated insulin secretion in human and mouse islets of Langerhans.
- 2016
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 59:4, s. 744-754
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Tidskriftsartikel (refereegranskat)abstract
- The Gq-coupled 5-hydroxytryptamine 2B (5-HT2B) receptor is known to regulate the proliferation of islet beta cells during pregnancy. However, the role of serotonin in the control of insulin release is still controversial. The aim of the present study was to explore the role of the 5-HT2B receptor in the regulation of insulin secretion in mouse and human islets, as well as in clonal INS-1(832/13) cells.
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| 8. |
- Bertonnier-Brouty, Ludivine, et al.
(författare)
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E2F transcription factors promote tumorigenicity in pancreatic ductal adenocarcinoma
- 2024
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Ingår i: Cancer Medicine. - 2045-7634. ; 13:9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, illustrating an urgent need to identify new drugable targets in PDACs.OBJECTIVE: Using the similarities between tumor development and normal embryonic development, which is accompanied by rapid cell expansion, we aimed to identify and characterize embryonic signaling pathways that were reinitiated during tumor formation and expansion.METHODS AND RESULTS: Here, we report that the transcription factors E2F1 and E2F8 are potential key regulators in PDAC. E2F1 and E2F8 RNA expression is mainly localized in proliferating cells in the developing pancreas and in malignant ductal cells in PDAC. Silencing of E2F1 and E2F8 in PANC-1 pancreatic tumor cells inhibited cell proliferation and impaired cell spreading and migration. Moreover, loss of E2F1 also affected cell viability and apoptosis with E2F expression in PDAC tissues correlating with expression of apoptosis and mitosis pathway genes, suggesting that E2F factors promote cell cycle regulation and tumorigenesis in PDAC cells.CONCLUSION: Our findings illustrate that E2F1 and E2F8 transcription factors are expressed in pancreatic progenitor and PDAC cells, where they contribute to tumor cell expansion by regulation of cell proliferation, viability, and cell migration making these genes attractive therapeutic targets and potential prognostic markers for pancreatic cancer.
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| 9. |
- Bsharat, Sara, et al.
(författare)
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MafB-dependent neurotransmitter signaling promotes β cell migration in the developing pancreas
- 2023
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Ingår i: Development: For advances in developmental biology and stem cells. - : The Company of Biologists. - 0950-1991. ; 150:6
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Tidskriftsartikel (refereegranskat)abstract
- Hormone secretion from pancreatic islets is essential for glucose homeostasis and loss or dysfunction of islet cells is a hallmark of type 2 diabetes. Maf transcription factors are critical for establishing and maintaining adult endocrine cell function. However, during pancreas development, MafB is not only expressed in insulin- and glucagon-producing cells, but also Neurog3+ endocrine progenitor cells suggesting additional functions in cell differentiation and islet formation. Here we report that MafB deficiency impairs β cell clustering and islet formation, but also coincides with loss of neurotransmitter and axon guidance receptor gene expression. Moreover, the observed loss of nicotinic receptor gene expression in human and mouse β cells implied that signaling through these receptors contributes to islet cell migration/formation. Inhibition of nicotinic receptor activity resulted in reduced β cell migration towards autonomic nerves and impaired β cell clustering. These findings highlight a novel function of MafB in controlling neuronal-directed signaling events required for islet formation.
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| 10. |
- Cataldo Bascuñan, Luis Rodrigo, et al.
(författare)
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Serotonergic Regulation of Insulin Secretion
- 2019
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1716 .- 1748-1708. ; 225:1
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Forskningsöversikt (refereegranskat)abstract
- The exact physiological role for the monoamine serotonin (5-HT) in modulation of insulin secretion is yet to be fully understood. Although the presence of this monoamine in islets of Langerhans is well established, it is only with recent advances that the complex signaling network in islets involving 5-HT is being unraveled. With more than fourteen different 5-HT receptors expressed in human islets, and receptor independent mechanisms in insulin producing β-cells, our understanding of 5-HT's regulation of insulin secretion is increasing. It is now widely accepted that failure of the pancreatic β-cell to release sufficient amounts of insulin is the main cause of Type 2 Diabetes (T2D), an ongoing global epidemic. In this context, 5-HT signaling may be of importance. In fact, 5-HT may serve an essential role in regulating the release of insulin and glucagon, the two main hormones that control glucose and lipid homeostasis. In the present review, we will discuss past and current understanding of 5-HT's role in the endocrine pancreas. This article is protected by copyright. All rights reserved.
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