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Cell Stem Cell. 2014 Aug 7;15(2):139-53. doi: 10.1016/j.stem.2014.06.019.

Loss of Fbw7 reprograms adult pancreatic ductal cells into α, δ, and β cells.

Author information

1
Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
2
Department of Cell and Developmental Biology, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
3
Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44, Lincoln's Inn Fields, London WC2A 3LY, UK; School of Medicine, King's College London, Guy's Campus, London SE1 1UL, UK. Electronic address: axel.behrens@cancer.org.uk.

Abstract

The adult pancreas is capable of limited regeneration after injury but has no defined stem cell population. The cell types and molecular signals that govern the production of new pancreatic tissue are not well understood. Here, we show that inactivation of the SCF-type E3 ubiquitin ligase substrate recognition component Fbw7 induces pancreatic ductal cells to reprogram into α, δ, and β cells. Loss of Fbw7 stabilized the transcription factor Ngn3, a key regulator of endocrine cell differentiation. The induced β cells resemble islet β cells in morphology and histology, express genes essential for β cell function, and release insulin after glucose challenge. Thus, loss of Fbw7 appears to reawaken an endocrine developmental differentiation program in adult pancreatic ductal cells. Our study highlights the plasticity of seemingly differentiated adult cells, identifies Fbw7 as a master regulator of cell fate decisions in the pancreas, and reveals adult pancreatic duct cells as a latent multipotent cell type.

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PMID:
25105579
PMCID:
PMC4136739
DOI:
10.1016/j.stem.2014.06.019
[Indexed for MEDLINE]
Free PMC Article
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