Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells.

Wang, T C; Bonner-Weir, Susan; Oates, Phillip S.; Chulak, M; Simon, Babette; Merlino, Glenn; Schmidt, Emmett V.; Brand, Stephen

doi:10.1172/jci116708

Cited by 261 publications

(196 citation statements)

References 33 publications

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“…This last point is reinforced by a recent report that, in transgenic mice overexpressing gastrin and transforming growth factor a (TGFa), islet neogenesis can be reactivated in the ductular epithelium by local expression of the two growth factors, gastrin and TGFa (26,27).…”

Section: Discussionmentioning

confidence: 97%

Expression of Reg and cytokeratin 20 during ductal cell differentiation and proliferation in a mouse model of autoimmune diabetes

Anastasi

Ponte²,

Gradini

et al. 1999

European Journal of Endocrinology

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Objective: To evaluate the existence of beta-cell differentiation and proliferation in the low-dose streptozotocin (ld-STZ) mouse model of autoimmune diabetes. Design: We studied the expression of Reg protein and cytokeratin 20 (CK20), the presence of proliferative phenomena (judged by the incorporation of bromodeoxyuridine (BrdU)), and the co-expression of Reg, CK20 or BrdU with insulin. Materials and methods: Diabetes was induced in male C57Bl6/J mice by administration of ld-STZ. The animals were killed at days 10 and 23 from the beginning of the induction of disease. Five animals were used at each time point and each group was evaluated for blood glucose concentrations, insulitis, expression of Reg and CK20 pancreatic proteins and BrdU incorporation, together with staining for insulin by immunohistochemistry and laser confocal microscopy. Results: All mice treated with ld-STZ were hyperglycemic and histological investigation showed a mild or severe insulitis both at day 10 and at day 23. At day 10, immunochemistry revealed an intense expression of Reg and CK20 in pancreatic ducts in ld-STZ mice, but not in control mice. Reg and CK20 immunoreactive cells were also positive for insulin. In contrast, at day 23, pancreatic sections reacted weakly with anti-Reg and anti-CK20 antibody; co-localization with insulin was observed for both Reg and CK20. The incorporation of BrdU was observed only in insulin-positive cells in pancreatic sections from mice killed at day 10. Conclusions: These observations show an islet regeneration mechanism in response to an autoimmune attack, and that the ld-STZ mouse is a suitable model in which to evaluate intervention strategies.

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Section: Discussionmentioning

confidence: 97%

Expression of Reg and cytokeratin 20 during ductal cell differentiation and proliferation in a mouse model of autoimmune diabetes

Anastasi

Ponte²,

Gradini

et al. 1999

European Journal of Endocrinology

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“…Other experimental treatments, including dietary soybean trypsin inhibitor [24], GLP-1 receptor agonists [25], betacellulin [26], and cellophane wrapping of the head of the pancreas (a partial duct obstruction) [27] have been reported to induce neogenesis. Additional strong evidence of formation of new β-cells by neogenesis comes from a number of transgenic models, including overexpression of interferon-γ in the β-cells [28], overexpression of transforming growth factor (TGF) α in pancreatic ducts [29], and Pax4 ectopic expression in glucagon-positive cells [30]. In the latter, β-cells are thought to originate from an α-cell lineage rather than a duct cell lineage.…”

Section: Experimental Models Of Neogenesismentioning

confidence: 99%

Islet Neogenesis: A Possible Pathway for Beta-Cell Replenishment

Bonner-Weir

Guo

Li³

et al. 2012

Rev Diabet Stud

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■ AbstractDiabetes, particularly type 1 diabetes, results from the lack of pancreatic β-cells. β-cell replenishment can functionally reverse diabetes, but two critical challenges face the field: 1. protection of the new β-cells from autoimmunity and allorejection, and 2. development of β-cells that are readily available and reliably functional. This chapter will examine the potential of endogenous replenishment of pancreatic β-cells as a possible therapeutic tool if autoimmunity could be blunted. Two pathways for endogenous replenishment exist in the pancreas: replication and neogenesis, defined as the formation of new islet cells from pancreatic progenitor/stem cells. These pathways of β-cell expansion are not mutually exclusive and both occur in embryonic development, in postnatal growth, and in response to some injuries. Since the β-cell population is dramatically reduced in the pancreas of type 1 diabetes patients, with only a small fraction of the β-cells surviving years after onset, replication of preexisting β-cells would not be a reasonable start for replenishment. However, induction of neogenesis could provide a starting population that could be further expanded by replication. It is widely accepted that neogenesis occurs in the initial embryonic formation of the endocrine pancreas, but its occurrence anytime after birth has become controversial because of discordant data from lineage tracing experiments. However, the concept was built upon many observations from different models and species over many years. Herein, we discuss the role of neogenesis in normal growth and regeneration, as learned from rodent models, followed by an analysis of what has been found in humans.

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“…One approach to identifying these factors is to demonstrate that mammalian genes contain RAP1 binding sites in DNA sequences controlling transcription. The gastrin gene is transiently expressed in fetal pancreatic islet cells and the encoded peptide is suggested to be involved in islet cell neogenesis [16,17]. This paper reports that both, the rat and human gastrin promoter contain a RAP1 binding site within a cis-regulatory domain controlling gastrin gene transcription in islet cells.…”

Section: Introductionmentioning

confidence: 99%

Activation of gastrin gene transcription in islet cells by a RAP1‐like cis‐acting promoter element

1994

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Gastrin transcription in islet cells is activated by a cis-regulatory sequence containing a binding site for the yeast transcription factor RAP1. The DNA-protein interactions between RAP1 protein and the gastrin DNA element determined by methylation interference assays are identical to those of RAP1 and yeast genes. Point mutations in the gastrin RAP1 binding site, which abolished RAP1 binding, decreased transcriptional activation by this sequence. Islet cells revealed a DNA binding protein with RAPl-like binding specificity. These findings support the conclusion that gastrin transcription is activated in mammalian cells by a RAPl-like transcription factor.

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Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells.

Cited by 261 publications

References 33 publications

Expression of Reg and cytokeratin 20 during ductal cell differentiation and proliferation in a mouse model of autoimmune diabetes

Expression of Reg and cytokeratin 20 during ductal cell differentiation and proliferation in a mouse model of autoimmune diabetes

Islet Neogenesis: A Possible Pathway for Beta-Cell Replenishment

Activation of gastrin gene transcription in islet cells by a RAP1‐like cis‐acting promoter element

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