In vivo genetic engineering of murine pancreatic beta cells mediated by single-stranded adeno-associated viral vectors of serotypes 6, 8 and 9

Jiménez, Verónica; Ayuso, Eduard; Mallol, Cristina; Agudo, Judith; Casellas, Alba; Obach, Mercè; Muñoz, Sergio; Salavert, Ariana; Bosch, Fátima

doi:10.1007/s00125-011-2070-3

Cited by 56 publications

(78 citation statements)

References 39 publications

(47 reference statements)

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“…34,35 However, one drawback with its use in the pancreas is inadequate labeling of pancreatic cells, especially pancreatic ductal cells. 24 Here we report that the combination of AAV serotype tissue tropism, with a specific gene promoter, together with ductal infusion of virus, leads to successful in vivo labeling of pancreatic ducts. After examining the entire pancreas of 15 wild-type CD1 mice infused with AAV6-Sox9-GFP, and 9 LSL-Tm reporter mice Figure 7 Lineage-tagging of ducts during acinar regeneration after caerulain treatment.…”

Section: Discussionmentioning

confidence: 99%

“…24 Therefore, we infused 100 ml of 2.35 Â 10 12 GCP/ml of AAV serotype 6 vector encoding ZsGreen (GFP) driven by the CMV promoter into the pancreas via cannulation of the common pancreatic/biliary duct in 10-week-old CD1 mice (Figure 2). At 3 days post infusion, expression of GFP throughout the pancreas and pancreatic ducts was seen (Figures 3a and b).…”

Section: Pancreatic Endocrine and Exocrine Cells Are Efficientlymentioning

confidence: 99%

“…8,23 To address the inherent problems associated with pancreatic duct labeling, especially the issues of low labeling efficiencies and unpredictable tamoxifen sensitivity, we utilized an adenoassociated virus (AAV serotype 6), ductal infusion approach. 24 Our goal here was to provide a better tool to more accurately assess for any ductal contribution to newly forming cells in different regeneration models. We first used a Sox9 promoter (468 bp short promoter) to generate a recombinant virus carrying a reporter GFP (AAV6-Sox9-GFP).…”

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confidence: 99%

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Specific transduction and labeling of pancreatic ducts by targeted recombinant viral infusion into mouse pancreatic ducts

Guo

Xiao

El-Gohary

et al. 2013

Laboratory Investigation

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Specific labeling of pancreatic ducts has proven to be quite difficult. Such labeling has been highly sought after because of the power it would confer to studies of pancreatic ductal carcinogenesis, as well as studies of the source of new insulinproducing b-cells. Cre-loxp recombination could, in theory, lineage-tag pancreatic ducts, but results have been conflicting, mainly due to low labeling efficiencies. Here, we achieved a high pancreatic duct labeling efficiency using a recombinant adeno-associated virus (rAAV) with a duct-specific sox9 promoter infused into the mouse common biliary/pancreatic duct. We saw rapid, diffuse duct-specific labeling, with 50 and 89% labeling in the pancreatic tail and head region, respectively. This highly specific labeling of ducts should greatly enhance our ability to study the role of pancreatic ducts in numerous aspects of pancreatic growth, development and function.

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Section: Discussionmentioning

confidence: 99%

Section: Pancreatic Endocrine and Exocrine Cells Are Efficientlymentioning

confidence: 99%

mentioning

confidence: 99%

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Specific transduction and labeling of pancreatic ducts by targeted recombinant viral infusion into mouse pancreatic ducts

Guo

Xiao

El-Gohary

et al. 2013

Laboratory Investigation

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“…Intraductal infusion was performed as has been previously described [7,8,9,10,11,12]. Briefly, the duodenum was isolated to expose the common bile duct, after which a microclamp was placed on the common bile duct above the branching of the pancreatic duct.…”

Section: Methodsmentioning

confidence: 99%

Modulation of FoxO1 Expression by miR-21 to Promote Growth of Pancreatic Ductal Adenocarcinoma

Shi

Wang

et al. 2015

Cell Physiol Biochem

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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal primary tumors in humans, with undetermined tumorigenesis. Although previous work by us, and by others, has clearly demonstrated an involvement of miR-21 in the growth of PDAC, the underlying mechanism has not been clarified. Methods: Here we analyzed the regulation of FoxO1 by miR-21 in vitro and in vivo, using luciferase-reporter assay and pancreatic intraductal infusion of antisense of miR-21, respectively. Results: We found that overexpression of miR-21 in PDAC cells decreased FoxO1 protein levels, whereas inhibition of miR-21 increased FoxO1 levels. Further, miR-21 bound to FoxO1 mRNA to prevent its translation through its 3'UTR. Moreover, administration of antisense of miR-21 through an intraductal infusion system significantly decreased miR-21 levels and increased FoxO1 levels in implanted PDAC, resulting in a significant decrease in PDAC growth. Conclusion: Taken together, our data highlight miR-21/FoxO1 axis as a novel therapeutic target for inhibiting the growth of PDAC.

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“…Numerous AAV serotypes are available with a natural tropism towards specific organs. For example AAV6, AVV8 and AVV9 have been shown to efficiently target the pancreatic islets in vivo [84]. In this context, the level of miR-26a which is downregulated in liver cancer cells has been corrected by administration of an AVV8 construct through the animal tail vein, resulting in a significant protection from hepatic cancer progression with no sign of toxicity [85].…”

Section: Replacement Therapymentioning

confidence: 99%

Therapeutic potential of miRNAs in diabetes mellitus

Henaoui

Stoll

Tugay

et al. 2014

Expert Review of Endocrinology & Metabolism

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SummaryMicroRNAs are major regulators of gene expression that are emerging as central players in the development of many human diseases, including diabetes mellitus. In fact, diabetes manifestation is associated with alterations in the microRNA profile in insulin-secreting cells, insulin target tissues and, in case of long-term diabetes complications, in many additional organs. Diabetes results also in changes in the profile of microRNAs detectable in blood and other body fluids. This has boosted an ever increasing interest in the use of circulating microRNAs as potential biomarkers to predict the development of diabetes and its devastating complications. Moreover, promising approaches to correct the level of selected microRNAs are emerging, permitting to envisage new therapeutic strategies to treat diabetes and its complications.Key words: Diabetes mellitus; Insulin; pancreatic islet; microRNA; Gene expression; biomarker; diabetic complication; Adeno-associated virus 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 of target mRNAs that are initially recognized through base pairing to a conserved "seed" sequence corresponding to nucleotides 2-8 of the miRNAs, leading to inhibition of mRNA translational and/or to a decrease in messenger stability [2, 3]. A single miRNA typically controls hundreds of targets and each mRNA can be targeted by different miRNAs, conferring to this class of non-coding RNA molecules a huge regulatory potential [4]. In the past decade, a large body of evidence has been accumulated pointing to a role for miRNAs in the etiology and pathogenesis of diabetes and its complications. Indeed, alterations in the level of these non-coding RNAs has been observed both in insulin-secreting cells and in insulin-target tissues isolated from diabetes animal models or diabetic patients [5]. Moreover, changes in miRNA expression have been associated with long-term diabetes complications including neuropathy, retinopathy, renal failure and macrovascular diseases. Page 1 of 36 Expert Review of Endocrinology & MetabolismThe first demonstration of the involvement of miRNAs in the control of specialized β-cell functions has been provided ten years ago by Poy et al. who showed that inappropriate levels of miR-375, one of the most abundant miRNAs present in β-cells, can affect insulin secretion [6]. Later on, this and several other miRNAs including miR-15a/b, miR-16, miR-195, miR-503, miR-451, miR-214, miR-9, miR-124a, miR-7 and miR-376 were demonstrated to play important roles in the differentiation of pancreatic islet cells [7][8][9][10][11][12]. Moreover, changes in the levels of many miRNAs, including miR-9, miR...

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In vivo genetic engineering of murine pancreatic beta cells mediated by single-stranded adeno-associated viral vectors of serotypes 6, 8 and 9

Cited by 56 publications

References 39 publications

Specific transduction and labeling of pancreatic ducts by targeted recombinant viral infusion into mouse pancreatic ducts

Specific transduction and labeling of pancreatic ducts by targeted recombinant viral infusion into mouse pancreatic ducts

Modulation of FoxO1 Expression by miR-21 to Promote Growth of Pancreatic Ductal Adenocarcinoma

Therapeutic potential of miRNAs in diabetes mellitus

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