β-cell neogenesis induced by adenovirus-mediated gene delivery of transcription factor pdx-1 into mouse pancreas

Taniguchi, H; Yamato, Eiji; Tashiro, Fumi; Ikegami, Hiromasa; Ogihara, Toshio; Miyazaki, Jun‐ichi

doi:10.1038/sj.gt.3301846

Cited by 108 publications

(70 citation statements)

References 51 publications

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“…In this procedure, the virus is directly injected into the pancreas through the common bile duct that drains the biliary and pancreatic fluid into the duodenum (Fig. 1A,B; Supplemental Movie 1; Taniguchi et al 2003;Wang et al 2006). Injection of adenoviral-CMV-Cre (Ad-Cre) into Cre reporter mice (R26 LSL-Tom ) (Madisen et al 2010) led to sporadic labeling of mostly acinar cells within the pancreas, with no detectable infection of cells within the liver, intestine, or any other organs outside the pancreas ( (Fig.…”

Section: Resultsmentioning

confidence: 99%

Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing

et al. 2015

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Pancreatic ductal adenocarcinoma (PDAC) is a genomically diverse, prevalent, and almost invariably fatal malignancy. Although conventional genetically engineered mouse models of human PDAC have been instrumental in understanding pancreatic cancer development, these models are much too labor-intensive, expensive, and slow to perform the extensive molecular analyses needed to adequately understand this disease. Here we demonstrate that retrograde pancreatic ductal injection of either adenoviral-Cre or lentiviral-Cre vectors allows titratable initiation of pancreatic neoplasias that progress into invasive and metastatic PDAC. To enable in vivo CRISPR/Cas9-mediated gene inactivation in the pancreas, we generated a Cre-regulated Cas9 allele and lentiviral vectors that express Cre and a single-guide RNA. CRISPR-mediated targeting of Lkb1 in combination with oncogenic Kras expression led to selection for inactivating genomic alterations, absence of Lkb1 protein, and rapid tumor growth that phenocopied Cre-mediated genetic deletion of Lkb1. This method will transform our ability to rapidly interrogate gene function during the development of this recalcitrant cancer.

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Section: Resultsmentioning

confidence: 99%

Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing

et al. 2015

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“…Accordingly, transgenic overexpression of PDX-1 restores beta cell mass and function, thereby preventing the onset of diabetes in IRS2-null mice [16]. Adenovirus-mediated Pdx-1 overexpression in the pancreas of the mouse favours beta cell neogenesis, whereas ectopic expression of Pdx-1 in mouse liver or human fetal liver progenitor cells promotes differentiation into insulin-producing cells [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

“…Pdx-1 plays an essential role in the regulation of beta cell neogenesis, differentiation and perhaps apoptosis [15][16][17][18]. Accordingly, transgenic overexpression of PDX-1 restores beta cell mass and function, thereby preventing the onset of diabetes in IRS2-null mice [16].…”

Section: Introductionmentioning

confidence: 99%

Suppression of Pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells

Wang¹,

Iezzi²,

Theander³

et al. 2005

Diabetologia

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Aims/hypothesis: Mutations in genes encoding HNF-4α, HNF-1α and IPF-1/Pdx-1 are associated with, respectively, MODY subtypes-1, -3 and -4. Impaired glucosestimulated insulin secretion is the common primary defect of these monogenic forms of diabetes. A regulatory circuit between these three transcription factors has also been suggested. We aimed to explore how Pdx-1 regulates beta cell function and gene expression patterns. Methods: We studied two previously established INS-1 stable cell lines permitting inducible expression of, respectively, Pdx-1 and its dominantnegative mutant. We used HPLC for insulin processing, adenovirally encoded aequorin for cytosolic [Ca 2+ ], and transient transfection of human growth hormone or patch-clamp capacitance recordings to monitor exocytosis. Results: Induction of DN-Pdx-1 resulted in defective glucose-stimulated and K + -depolarisation-induced insulin secretion in INS-1 cells, while overexpression of Pdx-1 had no effect. We found that DN-Pdx-1 caused down-regulation of fibroblast growth factor receptor 1 (FGFR1), and consequently prohormone convertases (PC-1/3 and -2). As a result, DN-Pdx-1 severely impaired proinsulin processing. In addition, induction of Pdx-1 suppressed the expression of glucagon-like peptide 1 receptor (GLP-1R), which resulted in marked reduction of both basal and GLP-1 agonist exendin-4-stimulated cellular cAMP levels. Induction of DN-Pdx-1 did not affect glucokinase activity, glycolysis, mitochondrial metabolism or ATP generation. The K + -induced cytosolic [Ca 2+ ] rise and Ca 2+-evoked exocytosis (membrane capacitance) were not abrogated. Conclusions/interpretation: The severely impaired proinsulin processing combined with decreased GLP-1R expression and cellular cAMP content, rather than metabolic defects or altered exocytosis, may contribute to the beta cell dysfunction induced by Pdx-1 deficiency.

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“…Administration of adenoviral vectors designed for expression of PDX-1 via the common bile duct was reported to induce neogenesis of pancreatic β cells in vivo [10]. Delivery of adenoviral vectors designed for expression of insulin gene enhancer protein-1, which is a transcription factor in addition to PDX-1, has been reported to promote the regenerative potential of pancreatic cells [11].…”

Section: Transgenes For the Treatment Of Diabetes Mellitusmentioning

confidence: 99%

Transgene and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus

Ookawara

Ishibashi

et al. 2017

Nano Reviews & Experiments

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Gene therapy that targets the pancreas and intestines with delivery systems using nano-sized carriers such as viral and non-viral vectors could improve the control of blood glucose levels, resulting in an improved prognosis for patients with diabetes mellitus. Allogenic pancreatic islet cell transplantations using such delivery systems have been developed as therapeutic options for diabetes mellitus. This review focuses on transgenes and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus.

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β-cell neogenesis induced by adenovirus-mediated gene delivery of transcription factor pdx-1 into mouse pancreas

Cited by 108 publications

References 51 publications

Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing

Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing

Suppression of Pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells

Transgene and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus

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