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Mol Ther. 2018 May 2;26(5):1327-1342. doi: 10.1016/j.ymthe.2018.02.014. Epub 2018 Feb 21.

Long-Term Correction of Diabetes in Mice by In Vivo Reprogramming of Pancreatic Ducts.

Author information

1
Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: wangyuh@ohsu.edu.
2
Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA.
3
Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA.
4
Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA; CEDAR Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
5
Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: grompem@ohsu.edu.

Abstract

Direct lineage reprogramming can convert readily available cells in the body into desired cell types for cell replacement therapy. This is usually achieved through forced activation or repression of lineage-defining factors or pathways. In particular, reprogramming toward the pancreatic β cell fate has been of great interest in the search for new diabetes therapies. It has been suggested that cells from various endodermal lineages can be converted to β-like cells. However, it is unclear how closely induced cells resemble endogenous pancreatic β cells and whether different cell types have the same reprogramming potential. Here, we report in vivo reprogramming of pancreatic ductal cells through intra-ductal delivery of an adenoviral vector expressing the transcription factors Pdx1, Neurog3, and Mafa. Induced β-like cells are mono-hormonal, express genes essential for β cell function, and correct hyperglycemia in both chemically and genetically induced diabetes models. Compared with intrahepatic ducts and hepatocytes treated with the same vector, pancreatic ducts demonstrated more rapid activation of β cell transcripts and repression of donor cell markers. This approach could be readily adapted to humans through a commonly performed procedure, endoscopic retrograde cholangiopancreatography (ERCP), and provides potential for cell replacement therapy in type 1 diabetes patients.

KEYWORDS:

Mafa; Neurog3; Pdx1; diabetes; gene therapy; insulin; liver; pancreas; reprogramming; β cell

PMID:
29550076
PMCID:
PMC5993989
DOI:
10.1016/j.ymthe.2018.02.014
[Indexed for MEDLINE]
Free PMC Article

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