Reprogramming Mouse Cells With a Pancreatic Duct Phenotype to Insulin-Producing β-Like Cells

Yamada, Takatsuga and Cavelti-Weder, Claudia and Caballero, Francisco and Lysy, Philippe A. and Guo, Lili and Sharma, Arun and Li, Weida and Zhou, Qiao and Bonner-Weir, Susan and Weir, Gordon C.. (2015) Reprogramming Mouse Cells With a Pancreatic Duct Phenotype to Insulin-Producing β-Like Cells. Endocrinology, 156 (6). pp. 2029-2038.

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Official URL: https://edoc.unibas.ch/61494/

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Reprogramming technology has opened the possibility of converting one cell type into another by forced expression of transgenes. Transduction of adenoviral vectors encoding 3 pancreatic transcription factors, Pdx1, Ngn3, and MafA, into mouse pancreas results in direct reprogramming of exocrine cells to insulin-producing beta-like cells. We hypothesized that cultured adult pancreatic duct cells could be reprogrammed to become insulin-producing beta-cells by adenoviral-mediated expression of this same combination of factors. Exocrine were isolated from adult mouse insulin 1 promoter (MIP)-green fluorescent protein (GFP) transgenic mice to allow new insulin-expressing cells to be detected by GFP fluorescence. Cultured cells were transduced by an adenoviral vector carrying a polycistronic construct Ngn3/Pdx1/MafA/mCherry (Ad-M3C) or mCherry sequence alone as a control vector. In addition, the effects of glucagon-like peptide-1 (GLP-1) receptor agonist, exendin-4 (Ex-4) on the reprogramming process were examined. GFP(+) cells appeared 2 days after Ad-M3C transduction; the reprogramming efficiency was 8.6 +/- 2.6% by day 4 after transduction. Ad-M3C also resulted in increased expression of beta-cell markers insulin 1 and 2, with enhancement by Ex-4. Expression of other beta-cell markers, neuroD and GLP-1 receptor, were also significantly up-regulated. The amount of insulin release into the media and insulin content of the cells were significantly higher in the Ad-M3C-transduced cells; this too was enhanced by Ex-4. The transduced cells did not secrete insulin in response to increased glucose, indicating incomplete differentiation to beta-cells. Thus, cultured murine adult pancreatic cells with a duct phenotype can be directly reprogrammed to insulin-producing beta-like cells by adenoviral delivery of 3 pancreatic transcription factors.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Translational Diabetes (Cavelti-Weder)
UniBasel Contributors:Cavelti-Weder, Claudia
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Oxford University Press; The Endocrine Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:16 Aug 2018 16:20
Deposited On:10 Jul 2018 16:25

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