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

Yuhan Wang, Craig Dorrell, Willscott E. Naugler, Michael Heskett, Paul Spellman, Bin Li, Feorillo Galivo, Annelise Haft, Leslie Wakefield, Markus Grompe

Research output: Contribution to journalArticle

9 Scopus citations

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. β cell regeneration has been of great interest in diabetes research. Wang et al. describe an intra-ductal injection approach to reprogram pancreatic ducts into insulin-producing β cells and rescue diabetes in mouse models. This work provides important insights into the mechanism of reprogramming and offers a promising therapeutic strategy for type 1 diabetes.

Original languageEnglish (US)
Pages (from-to)1327-1342
Number of pages16
JournalMolecular Therapy
Volume26
Issue number5
DOIs
StatePublished - May 2 2018

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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