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.
| Original language | English |
|---|---|
| Pages (from-to) | 139-153 |
| Number of pages | 15 |
| Journal | Cell Stem Cell |
| Volume | 15 |
| Issue number | 2 |
| Early online date | 7 Aug 2014 |
| DOIs | |
| Publication status | Published - 7 Aug 2014 |
Keywords
- Basic Helix-Loop-Helix Transcription Factors/genetics
- Cell Differentiation
- Cell Lineage
- F-Box Proteins/genetics
- F-Box-WD Repeat-Containing Protein 7
- Gene Deletion
- Gene Expression Profiling
- Gene Expression Regulation, Developmental
- Glucagon-Secreting Cells/cytology
- Glucose/metabolism
- HEK293 Cells
- Insulin/metabolism
- Insulin Secretion
- Insulin-Secreting Cells/cytology
- Multipotent Stem Cells/cytology
- Nerve Tissue Proteins/genetics
- Pancreatic Ducts/cytology
- Proteasome Endopeptidase Complex/metabolism
- Regeneration/genetics
- Somatostatin-Secreting Cells/cytology
- Ubiquitin-Protein Ligases/genetics
- Ubiquitination