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

Abstract

SummaryThe 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.

Out of the F-box: Reawakening the Pancreas

“…Conditional transgenic expression of a phosphodegron mutant Ngn3, in the presence of endogenously expressed Fbxw7, quickly (within 24 hours) resulted in the emergence of insulinpositive β-cells in the pancreas. Together with the results from the pancreas conditional deletion of Fbxw7 , these findings suggest that the β-cells arise through direct conversion of ductal cells, rather than an intermediate progenitor cell that divides prior to differentiation (Sancho et al, 2014). …”

“…In this issue, Sancho et al (2014) show that pancreas-specific loss of the ubiquitin ligase Fbxw7 stabilizes an endocrine-specific transcription factor, Ngn3, thus inducing in vivo β-cell neogenesis. …”

Immunophenotypes of Ductal Epithelial Cells in Advanced Pancreatic Ductal Adenocarcinoma

“…-/-HCT116 cell line shows that endogenous deletion of ubiquitin ligase Fbxw7 in pancreas may promote the stability of isletspecific transcription factor Ngn3, thereby inducing pancreatic β cell regeneration [20]. In Fbxw7-deleted pancreatic ducts, Ngn3 is activated and stabilized transcription of downstream effectors that regulate β cell differentiation.…”

Bringing together the organoid field: from early beginnings to the road ahead

“…She presented her findings on the role played by the E3 ubiquitin ligase Fbw7 (Fbxw7) in beta cell specification and reprogramming (Sancho et al, 2014). She showed how the loss of Fbw7 in CK19 (Krt19) + adult pancreatic ductal cells in vivo resulted in stabilization of the transcription factor Ngn3 (Neurog3), a regulator of endocrine differentiation, which led to reprogramming of ductal cells to insulin-secreting beta cells.…”