Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3

Heremans, Yves; Casteele, Mark Van de; Veld, Peter In’t; Gradwohl, Gérard; Serup, Palle; Madsen, Ole; Pipeleers, Daniël; Heimberg, Harry

doi:10.1083/jcb.200203074

Cited by 251 publications

(220 citation statements)

References 43 publications

Supporting

Mentioning

212

Contrasting

Unclassified

Order By: Relevance

“…15,16,28 Ectopic expression of Ngn3 in adult exocrine ductal cells leads to a partial recapitulation of endocrine differentiation. 19 In normal pancreas, freshly isolated exocrine tissue and cultured exocrine cells, Ngn3 mRNA was absent. Our study demonstrates that stimulation of the exocrine cells with both EGF and LIF activated Ngn3 gene expression.…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Ngn3 expression during postnatal in vitro beta cell neogenesis induced by the JAK/STAT pathway

Baeyens¹,

Bonné²,

German³

et al. 2006

Cell Death Differ

View full text Add to dashboard Cite

The basic helix-loop-helix protein Neurogenin3 specifies precursor cells of the endocrine pancreas during embryonic development, and is thought to be absent postnatally. We have studied Ngn3 expression during in vitro generation of beta-cells from adult rat exocrine pancreas tissue treated with epidermal growth factor and leukaemia inhibitory factor. This treatment induced a transient expression of both Ngn3 and its upstream activator hepatocyte nuclear factor 6. Inhibition of EGF and LIF signalling by pharmacological antagonists of the JAK2/STAT3 pathway, or knockdown of Ngn3 by RNA interference prevented the generation of new insulin-positive cells. This study demonstrates that in vitro growth factor stimulation can induce recapitulation of an embryonic endocrine differentiation pathway in adult dedifferentiated exocrine cells. This could prove to be important for understanding the mechanism of beta-cell regeneration and for therapeutic ex vivo neogenesis of beta cells. Keywords: neurogenin3; transdifferentiation; beta cell; pancreas; diabetes Abbreviations: CK20, cytokeratin 20; EGF, epidermal growth factor; eGFP, enhanced green fluorescent protein; Hnf6, hepatocyte nuclear factor 6; JAK2, Janus kinase 2; LIF, leukaemia inhibitory factor; Ngn3, neurogenin 3; Pdx1, pancreatic and duodenal homeobox 1; STAT3, signal transducer and activator of transcription 3 IntroductionThere is currently a lot of interest in the development of a treatment for diabetes that is based on beta-cell replacement or regeneration. Beta-cells could be (re-)generated by stimulation of beta-cell replication and/or (trans-)differentiation of stem/progenitor cells. It has been demonstrated that, during adult life, beta-cell maintenance and compensatory growth in mice results primarily from proliferation of the pre-existing beta cells. 1 However, numerous reports of alternative sources of beta-cell 'neogenesis' in response to severe tissue injury have been described. [2][3][4][5][6] The pancreas is composed of exocrine tissue, comprising acinar and duct cells, and of endocrine tissue that contains beta-, alpha-, delta-and pancreatic polypeptide cells. A possible source of progenitor cells is the acinar cell population that is the most abundant in adult pancreas and is known to retain a remarkable plasticity both in vivo and in vitro. 7-9 Isolated acinar cells can undergo dedifferentiation in vitro whereby they lose their zymogen granules and gain a duct-like phenotype including expression of the duct cell marker cytokeratin20. 8,10 External stimuli can induce a phenotypical switch in these cells towards a hepatocyte-like phenotype. 7 We have recently developed a model for in vitro beta-cell neogenesis based upon growth factor stimulation of dedifferentiated acinar pancreatic cells. 11 The molecular regulation of this transdifferentiation from acinar to beta cells is unknown at present. Although it is known that during pancreatic regeneration the exocrine population can dedifferentiate towards an embryonic-like state in vivo, 12 in v...

show abstract

Section: Discussionmentioning

confidence: 98%

“…16 Additionally, ectopic expression of Ngn3 predestines embryonic endoderm to an endocrine fate. 13,[17][18][19] In adult pancreas, Ngn3 is no longer expressed, or it is expressed at very low level. 15 It is not known whether re-expression of Ngn3 occurs in adult cells during regeneration.…”

Section: Introductionmentioning

confidence: 99%

Ngn3 expression during postnatal in vitro beta cell neogenesis induced by the JAK/STAT pathway

Baeyens¹,

Bonné²,

German³

et al. 2006

Cell Death Differ

View full text Add to dashboard Cite

show abstract

“…Another intriguing finding was the up-regulation of Notch1, delta-1 (both induced by dsRNA + IFN-γ at 6 h), and of presenilin-2 (induced by dsRNA and IFN-γ at 24 h). Delta-1 is a ligand of the Notch receptor, while presenilins-1 and 2 are enzymes responsible for the intramembraneous proteolysis and activation of Notch [74,76,77,78]. Differentiation is inhibited in endocrine precursor cells expressing activated Notch receptors, whereas the signalling cells (expressing delta-1) are free to differentiate into endocrine cells [74].…”

Section: Discussionmentioning

confidence: 99%

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

et al. 2003

View full text Add to dashboard Cite

Aims/hypothesis. Viral infections and local production of IFN-γ might contribute to beta-cell dysfunction/ death in Type 1 Diabetes. Double stranded RNA (dsRNA) accumulates in the cytosol of viral-infected cells, and exposure of purified rat beta cells to dsRNA (tested in the form of polyinosinic-polycytidylic acid, PIC) in combination with IFN-γ results in beta-cell dysfunction and apoptosis. To elucidate the molecular mechanisms involved in PIC + IFN-γ-effects, we determined the global profile of genes modified by these agents in primary rat beta cells. Methods. FACS-purified rat beta cells were cultured for 6 or 24 h in control condition or with IFN-γ, PIC or a combination of both agents. The gene expression profile was analysed in duplicate by high-density oligonucleotide arrays representing 5000 full-length genes and 3000 EST's. Changes of greater than or equal to 2.5-fold were considered as relevant.Results. Following a 6-or 24-h treatment with IFN-γ, PIC or IFN-γ and PIC, we observed changes in the expression of 51 to 189 genes. IFN-γ modified the expression of MHC-related genes, and also of genes involved in beta-cell metabolism, protein processing, cytokines and signal transduction. PIC affected preferentially the expression of genes related to cell adhesion, cytokines and dsRNA signal transduction, transcription factors and MHC. PIC and/or IFN-γ up-regulated the expression of several chemokines and cytokines that could contribute to mononuclear cell homing and activation during viral infection, while IFN-γ induced a positive feedback on its own signal transduction. PIC + IFN-γ inhibited insulin and GLUT-2 expression without modifying pdx-1 mRNA expression. Conclusion/interpretation. This study provides the first comprehensive characterization of the molecular responses of primary beta cells to dsRNA + IFN-γ, two agents that are probably present in the beta cell milieu during the course of virally-induced insulitis and Type 1 Diabetes. Based on these findings, we propose an integrated model for the molecular mechanisms involved in dsRNA + IFN-γ induced beta-cell dysfunction and death. [Diabetologia (2003[Diabetologia ( ) 46:1641[Diabetologia ( -1657

show abstract

“…A recent study suggests that Pdx1, in complex with TALE transcription factors, negatively regulates the duct-specific keratin 19 gene in mature duct cells [100]. This finding raises the possibility that enhanced levels of Pdx1 protein in duct cells may promote β cell transdifferentiation by direct repression of the duct cell phenotype (through suppression of keratin 19 and related genes) and simultaneous activation of β cell-specific genes [101][102][103]. Currently, there is little evidence that any other cell type contributes to β cell neogenesis.…”

Section: Role Of Pdx1 In Adaptive β Cell Hyperplasia and β Cell Regenmentioning

confidence: 99%

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Babu

Deering

Mirmira

2007

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

Emerging evidence over the past decade indicates a central role for transcription factors in the embryonic development of pancreatic islets and the consequent maintenance of normal glucose homeostasis. Pancreatic and duodenal homeobox 1 (Pdx1) is the best studied and perhaps most important of these factors. Whereas deletion or inactivating mutations of the Pdx1 gene causes whole pancreas agenesis in both mice and humans, even haploinsufficiency of the gene or alterations in its expression in mature islet cells causes substantial impairments in glucose tolerance and the development of a late-onset form of diabetes known as maturity onset diabetes of the young. The study of Pdx1 has revealed crucial phenotypic interrelationships of the varied cell types within the pancreas, particularly as these impinge upon cellular differentiation in the embryo and neogenesis and regeneration in the adult. In this review, we describe the actions of Pdx1 in the developing and mature pancreas and attempt to unify these actions with its known roles in modulating transcriptional complex formation and chromatin structure at the molecular genetic level.

show abstract

Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3

Cited by 251 publications

References 43 publications

Ngn3 expression during postnatal in vitro beta cell neogenesis induced by the JAK/STAT pathway

Ngn3 expression during postnatal in vitro beta cell neogenesis induced by the JAK/STAT pathway

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Contact Info

Product

Resources

About