Loss of Fbw7 Reprograms Adult Pancreatic Ductal Cells into α, δ, and β Cells

• DOI: 10.1016/j.stem.2014.06.019
• Publication Date: 2014-08-07T15:46:57Z
• Authors: Rocio Sancho; Ralph Gruber; Guoqiang Gu; Axel Behrens
• Keywords: F-Box-WD Repeat-Containing Protein 7; Insulin/metabolism; 610; Nerve Tissue Proteins; Article; Glucagon-Secreting Cells/cytology; Mice; Insulin-Secreting Cells/cytology; Cell Line, Tumor; Insulin-Secreting Cells; Insulin Secretion; Genetics; Basic Helix-Loop-Helix Transcription Factors; Glucose/metabolism; Nerve Tissue Proteins/genetics; Animals; Humans; Insulin; Developmental; Cell Lineage; Ubiquitin-Protein Ligases/genetics; Basic Helix-Loop-Helix Transcription Factors/genetics; Pancreatic Ducts/cytology; F-Box Proteins; Gene Expression Profiling; Multipotent Stem Cells; Ubiquitination; Gene Expression Regulation, Developmental; Cell Differentiation; Cell Biology; Somatostatin-Secreting Cells/cytology; Proteasome Endopeptidase Complex/metabolism; Glucose; HEK293 Cells; Gene Expression Regulation; Glucagon-Secreting Cells; F-Box Proteins/genetics; Molecular Medicine; Regeneration/genetics; Multipotent Stem Cells/cytology; Gene Deletion

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.