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Modeling human pancreatic beta cell dedifferentiation.

ABSTRACT: OBJECTIVE:Dedifferentiation could explain reduced functional pancreatic ?-cell mass in type 2 diabetes (T2D). METHODS:Here we model human ?-cell dedifferentiation using growth factor stimulation in the human ?-cell line, EndoC-?H1, and human pancreatic islets. RESULTS:Fibroblast growth factor 2 (FGF2) treatment reduced expression of ?-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 ?-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. CONCLUSIONS:We thus developed an FGF2-induced model of human ?-cell dedifferentiation, identified new markers of dedifferentiation, and found evidence for increased pancreatic FGF2, FGFR1, and ?-cell dedifferentiation in T2D.

SUBMITTER: Diedisheim M

PROVIDER: S-EPMC5985229 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Modeling human pancreatic beta cell dedifferentiation.

Diedisheim Marc M Oshima Masaya M Albagli Olivier O Huldt Charlotte Wennberg CW Ahlstedt Ingela I Clausen Maryam M Menon Suraj S Aivazidis Alexander A Andreasson Anne-Christine AC Haynes William G WG Marchetti Piero P Marselli Lorella L Armanet Mathieu M Chimienti Fabrice F Scharfmann Raphael R

Molecular metabolism 20180208

<h4>Objective</h4>Dedifferentiation could explain reduced functional pancreatic β-cell mass in type 2 diabetes (T2D).<h4>Methods</h4>Here we model human β-cell dedifferentiation using growth factor stimulation in the human β-cell line, EndoC-βH1, and human pancreatic islets.<h4>Results</h4>Fibroblast 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 dedifferen ...[more]

PMID: 29472102

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Project description:Maintenance of the pancreatic acinar cell phenotype suppresses tumor formation. Hence, repetitive acute or chronic pancreatitis, stress conditions in which the acinar cells dedifferentiate, predispose for cancer formation in the pancreas. Dedifferentiated acinar cells acquire a large panel of duct cell-specific markers. However, it remains unclear to what extent dedifferentiated acini differ from native duct cells and which genes are uniquely regulating acinar cell dedifferentiation. Moreover, most studies have been performed on mice since the availability of human cells is scarce. Here, we applied a non-genetic lineage tracing method of human pancreatic exocrine acinar and duct cells that allowed cell-type-specific gene expression profiling by RNA sequencing. Subsequent to this discovery analysis, one transcription factor that was unique for dedifferentiated acinar cells was functionally characterized. RNA sequencing analysis showed that human dedifferentiated acinar cells expressed genes in "Pathways of cancer" with a prominence of MECOM (EVI-1), a transcription factor that was not expressed by duct cells. During mouse embryonic development, pre-acinar cells also transiently expressed MECOM and in the adult mouse pancreas, MECOM was re-expressed when mice were subjected to acute and chronic pancreatitis, conditions in which acinar cells dedifferentiate. In human cells and in mice, MECOM expression correlated with and was directly regulated by SOX9. Mouse acinar cells that, by genetic manipulation, lose the ability to upregulate MECOM showed impaired cell adhesion, more prominent acinar cell death, and suppressed acinar cell dedifferentiation by limited ERK signaling. In conclusion, we transcriptionally profiled the two major human pancreatic exocrine cell types, acinar and duct cells, during experimental stress conditions. We provide insights that in dedifferentiated acinar cells, cancer pathways are upregulated in which MECOM is a critical regulator that suppresses acinar cell death by permitting cellular dedifferentiation.

Dataset Information

Modeling human pancreatic beta cell dedifferentiation.

Publications

Modeling human pancreatic beta cell dedifferentiation.

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