Modeling human pancreatic beta cell dedifferentiation

Abstract

ObjectiveDedifferentiation could explain reduced functional pancreatic β-cell mass in type 2 diabetes (T2D).MethodsHere we model human β-cell dedifferentiation using growth factor stimulation in the human β-cell line, EndoC-βH1, and human pancreatic islets.ResultsFibroblast growth factor 2 (FGF2) treatment reduced expression of β-cell markers, (INS, MAFB, SLC2A2, SLC30A8, and GCK) and activated ectopic expression of MYC, HES1, SOX9, and NEUROG3. FGF2-induced dedifferentiation was time- and dose-dependent and reversible upon wash-out. Furthermore, FGF2 treatment induced expression of TNFRSF11B, a decoy receptor for RANKL and protected β-cells against RANKL signaling. Finally, analyses of transcriptomic data revealed increased FGF2 expression in ductal, endothelial, and stellate cells in pancreas from T2D patients, whereas FGFR1, SOX,9 and HES1 expression increased in islets from T2D patients.ConclusionsWe thus developed an FGF2-induced model of human β-cell dedifferentiation, identified new markers of dedifferentiation, and found evidence for increased pancreatic FGF2, FGFR1, and β-cell dedifferentiation in T2D.

Beta-Cell Dedifferentiation in Type 2 Diabetes: Concise Review

“…A recent study evaluating the utility of EndoC‐βH1 cells, a transformed human β‐cell line, as a model for β‐cell dedifferentiation , suggested that these cells could serve for initial screening of factors altering normal β‐cell gene expression. The study found that increased FGF signaling led to decreased expression of β‐cell markers, and activation of progenitor‐cell markers, such as SOX9 and HES1.…”

Small Molecule-Induced Pancreatic β-Like Cell Development: Mechanistic Approaches and Available Strategies

“…They can efficiently promote cell differentiation and govern other cellular activities like common promoters and growth factors which are expensive, and can be harmful. Small molecules are cell permeable chemical compounds which are generally safer, inexpensive, pure, amenable to scaling up, and are devoid of animal derived products which makes them more suitable candidates to be used in in vitro practices [29][30][31][32]. The main motivation behind using small molecules is that they can be synthesized in large amounts with higher purity and stored in a way that ensures their reproducible activity [30].…”

The supply chain of human pancreatic β cell lines

“…Peptidomic-based approaches have also used the human β cell lines to identify target epitopes processed and presented by β cells, thereby providing the first HLA-I peptidome catalog of human β cells (84). Finally, our group used EndoC-βH1 cells to develop models and identify markers of human β cell dedifferentiation (85,86). All of the above examples depended on experiments that would have been difficult to perform with human islets because of limitations in cell purity or cell number and that would have produced different results in rodent β cell lines because of species differences.…”