人胰腺β细胞去分化建模。
Modeling human pancreatic beta cell dedifferentiation.
机构信息
INSERM U1016, Institut Cochin, Université Paris Descartes, 123 Boulevard de Port-Royal, 75014 Paris, France.
Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden.
出版信息
Mol Metab. 2018 Apr;10:74-86. doi: 10.1016/j.molmet.2018.02.002. Epub 2018 Feb 8.
OBJECTIVE
Dedifferentiation could explain reduced functional pancreatic β-cell mass in type 2 diabetes (T2D).
METHODS
Here we model human β-cell dedifferentiation using growth factor stimulation in the human β-cell line, EndoC-βH1, and human pancreatic islets.
RESULTS
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 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.
CONCLUSIONS
We 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.
目的
去分化可以解释 2 型糖尿病（T2D）中功能性胰腺β细胞质量的减少。
方法
在这里，我们使用生长因子刺激人β细胞系 EndoC-βH1 和人胰腺胰岛来模拟人β细胞去分化。
结果
成纤维细胞生长因子 2（FGF2）处理降低了β细胞标志物（INS、MAFB、SLC2A2、SLC30A8 和 GCK）的表达，并激活了 MYC、HES1、SOX9 和 NEUROG3 的异位表达。FGF2 诱导的去分化是时间和剂量依赖性的，并且在冲洗后可逆转。此外，FGF2 处理诱导了 TNFRSF11B 的表达，TNFRSF11B 是 RANKL 的诱饵受体，可保护β细胞免受 RANKL 信号的影响。最后，对转录组数据的分析显示，T2D 患者胰腺中的导管、内皮和星状细胞中 FGF2 的表达增加，而 T2D 患者胰岛中的 FGFR1、SOX9 和 HES1 的表达增加。
结论
因此，我们开发了一种 FGF2 诱导的人β细胞去分化模型，鉴定了新的去分化标志物，并发现了 T2D 中胰腺 FGF2、FGFR1 和β细胞去分化增加的证据。
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