Transgenic expression of epidermal growth factor and keratinocyte growth factor in beta-cells results in substantial morphological changes

Krakowski, Michelle; Kritzik, Marcie; Jones, Ellene M.; Krahl, Troy; Lee, J; Arnush, Marc; Gu, Danling; Mroczkowski, Barbara; Sarvetnick, Nora

doi:10.1677/joe.0.1620167

Cited by 61 publications

(34 citation statements)

References 33 publications

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“…Also in agreement with our previous results is the lack of pathological alterations in PIP-hBTC transgenic mice. This is in contrast to the multiple pathological effects including islet disaggregation, fibrosis, and even ductal metaplasia observed in transgenic mice with -cell-specific overexpression of the EGFR ligands EGF (Krakowski et al 1999) and heparin-binding EGF (Means et al 2003). This observation indicates that BTC has unique actions on pancreatic islets as compared to other EGFR ligands.…”

Section: Discussionmentioning

confidence: 82%

“…The rat (Dahl et al 1996;Hanahan 1985;Vasavada et al 1996), mouse (Hara et al 2003), and human (Hotta et al 1998;Krakowski et al 1999) insulin promoters have been frequently used to direct expression of oncogenes, hormones, growth factors, transcription factors, reporter genes, and more recently of the enzyme Cre recombinase (Ahlgren et al 1998;Dor et al 2004;Gannon et al 2000;Postic et al 1999) specifically to pancreatic -cells in transgenic mice. A major caveat of the rat insulin promoter, however, is the reported ectopic expression in certain areas of the brain, potentially resulting in phenotypes in both -cells and neural cells (Gannon et al 2000;Martin et al 2003).…”

Section: Introductionmentioning

confidence: 99%

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Specific transgene expression in mouse pancreatic β-cells under the control of the porcine insulin promoter

Grzech¹,

Dahlhoff²,

Herbach³

et al. 2010

Molecular and Cellular Endocrinology

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The availability of regulatory sequences directing tissue-specific expression of transgenes in genetically modified mice and large animals is a prerequisite for the development of adequate models for human diseases. The rat insulin 2 gene (Ins2) promoter, widely used to achieve transgene expression in pancreatic -cells of mice, also directs expression to extrapancreatic tissues and performs poorly in isolated pancreatic islets of human, mouse, and pig. To evaluate whether the full 5' untranslated region (UTR) of the porcine insulin gene (INS) confers robust and specific expression in -cells we generated an expression cassette containing 1500 bp of the porcine INS 5' UTR and the 3' UTR of the bovine growth hormone gene (GH). The cassette was designed to allow easy exchange of the sequences to be expressed and easy removal of the vector backbone from the expression cassette. To evaluate the properties of the cassette, we initially cloned a cDNA encoding human betacellulin, a growth factor known to affect structural and functional parameters of -cells. After confirming the functionality and specificity of the construct in vitro, transgenic mouse lines were generated by pronuclear DNA microinjection. Using RT-PCR, immunohistochemistry and immunofluorescence, we show that transgenic mice expressed human betacellulin exclusively in -cells. Confirming the proposed insulinotropic effect of betacellulin, transgenic mice showed improved glucose tolerance. We conclude that the newly designed expression cassette containing 1.500 bp of the porcine insulin promoter 5' UTR confers robust and specific transgene expression to -cells in vitro and in transgenic mice.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Specific transgene expression in mouse pancreatic β-cells under the control of the porcine insulin promoter

Grzech¹,

Dahlhoff²,

Herbach³

et al. 2010

Molecular and Cellular Endocrinology

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“…The expression of this growth factor and its receptors is up-regulated in pancreatic carcinomas [17]. Studies in transgenic mice expressing KGF alone [18] or both KGF and EGF [19] in their beta cells showed that ectopic expression of KGF in the pancreas induces increased ductal-cell proliferation, profound changes in pancreatic morphology and the appearance of hepatocytes within the Fig. 4A, B.…”

Section: Effect Of Kgf On Beta Cell and Ductal Cell Proliferationmentioning

confidence: 97%

Keratinocyte growth factor and beta-cell differentiation in human fetal pancreatic endocrine precursor cells

et al. 2003

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Aims and hypothesis. Keratinocyte growth factor (KGF) is a member of the heparin-binding fibroblast growth factor family with a high degree of specificity for epithelial cells in vitro and in vivo. Our aim was to study the effect of KGF on beta-cell growth and differentiation on islet-like cell clusters derived from human fetal pancreas. Methods. We investigated the effects of KGF, in vitro, on beta-cell differentiation from undifferentiated pancreatic precursor cells and in vivo after transplantating human fetal pancreatic cells into athymic rats treated with KGF. Results. Treatment of islet-like cell clusters with KGF in vitro did not change the number of insulin producing cells, as measured by the measurement of insulin content or DNA. The in vivo treatment of recipient rats with KGF increased the number of beta cells within the grafts 8 weeks after transplantation. At this time, glucose-stimulated insulin secretion was evaluated by glucose stimulation tests in rats bearing the transplants. Measurements of human C-peptide concentrations after glucose challenge showed that the newly differentiated beta cells in the KGF-treated group were functionally competent as opposed to the control group, where the graft failed to release insulin appropriately. Conclusion/interpretation. These findings suggest that in vivo, KGF is capable of inducing human fetal beta-cell expansion. The growth promoting effect of KGF on beta cells occurred mainly through the activation of ductal cell proliferation and their subsequent differentiation into beta cells. [Diabetologia (2003) 46:822-829]

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“…Interestingly, studies on isolated islets suggest that EGF ligands have little mitogenic effect in culture (Sjoholm 1996). However, in vivo b-cell-specific overexpression of EGF leads to increased b-cell proliferation (Krakowski et al 1999). These contrasting effects may reflect a differential response of the islet to the microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Epidermal growth factor induces adult human islet cell dedifferentiation

Hanley¹,

Assouline-Thomas²,

Makhlin³

et al. 2011

Journal of Endocrinology

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Given the inherent therapeutic potential of the morphogenetic plasticity of adult human islets, the identification of factors controlling their cellular differentiation is of interest. The epidermal growth factor (EGF) family has been identified previously in the context of pancreatic organogenesis. We examined the role of EGF in an in vitro model whereby adult human islets are embedded in a collagen gel and dedifferentiated into duct-like epithelial structures (DLS). We demonstrated that DLS formation was EGF dependent, while residual DLS formation in the absence of added EGF was abrogated by EGF receptor inhibitor treatment. With respect to signaling, EGF administration led to an increase in c-Jun NH2-terminal kinase (JNK) phosphorylation early in DLS formation and in AKT and extracellular signalregulated kinase (ERK) phosphorylation late in the process of DLS formation, concomitant with the increased proliferation of dedifferentiated cells. In the absence of EGF, these phosphorylation changes are not seen and the typical increase in DLS epithelial cell proliferation seen after 10 days in culture is attenuated. Thus, in our model, EGF is necessary for islet cell dedifferentiation, playing an important role in both the onset of DLS formation (through JNK) and in the proliferation of these dedifferentiated cells (through AKT and ERK).

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Transgenic expression of epidermal growth factor and keratinocyte growth factor in beta-cells results in substantial morphological changes

Cited by 61 publications

References 33 publications

Specific transgene expression in mouse pancreatic β-cells under the control of the porcine insulin promoter

Specific transgene expression in mouse pancreatic β-cells under the control of the porcine insulin promoter

Keratinocyte growth factor and beta-cell differentiation in human fetal pancreatic endocrine precursor cells

Epidermal growth factor induces adult human islet cell dedifferentiation

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