Small-molecule inhibitors of the cystic fibrosis transmembrane conductance regulator increase pancreatic endocrine cell development in rat and mouse.
Small-molecule inhibitors of the cystic fibrosis transmembrane conductance regulator increase pancreatic endocrine cell development in rat and mouse.
复制标题
囊性纤维化跨膜电导调节剂的小分子抑制剂可增加大鼠和小鼠的胰腺内分泌细胞发育。
DOI：
10.1007/s00125-012-2778-8
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发表时间：
2013
期刊：
影响因子：
8.2
通讯作者：
Scharfmann,R
中科院分区：
文献类型：
--
作者：
Zertal-Zidani,S;Busiah,K;Edelman,A;Polak,M;Scharfmann,R
Aims/hypothesis这项工作的主要目的是发现新的药物，可以激活多能胰腺祖细胞分化成内分泌cells.MethodsIn体外实验进行了使用大鼠和小鼠的胎儿胰腺外植体。在本试验中，我们研究了格列本脲（磺酰脲衍生物）和甘氨酸酰肼（GlyH-101）（囊性纤维化跨膜传导调节因子（CFTR）的小分子抑制剂）对胰腺细胞发育的作用。我们接下来测试了GlyH-101对体内胰腺细胞发育的作用。结果格列本脲（10 nmol/l-100 μmol/l）没有改变发育中胰腺的形态或生长，也没有对胰腺外分泌细胞发育产生有害影响。出乎意料的是，最高浓度的格列本脲促进了内分泌分化。当使用其他磺脲类药物时，格列本脲诱导的内分泌途径促进作用无法重现，表明格列本脲具有脱靶作用。此前曾报道过这种高浓度的格列本脲可抑制CFTR。我们发现格列本脲对发育中胰腺的作用可以在体外和体内被GlyH-101模拟。结论/解释总的来说，我们证明了两种CFTR的小分子抑制剂格列本脲和GlyH-101通过增加发育中胰腺中神经生成素3阳性内分泌祖细胞库的大小来增加胰腺内分泌细胞的数量。
Aims/hypothesisThe main objective of this work was to discover new drugs that can activate the differentiation of multipotent pancreatic progenitors into endocrine cells.MethodsIn vitro experiments were performed using fetal pancreatic explants from rats and mice. In this assay, we examined the actions on pancreatic cell development of glibenclamide, a sulfonylurea derivative, and glycine hydrazide (GlyH-101), a small-molecule inhibitor of cystic fibrosis transmembrane conductance regulator (CFTR). We next tested the actions of GlyH-101 on in vivo pancreatic cell development.ResultsGlibenclamide (10 nmol/l–100 μmol/l) did not alter the morphology or growth of the developing pancreas and exerted no deleterious effects on exocrine cell development in the pancreas. Unexpectedly, glibenclamide at its highest concentration promoted endocrine differentiation. This glibenclamide-induced promotion of the endocrine pathway could not be reproduced when other sulfonylureas were used, suggesting that glibenclamide had an off-target action. This high concentration of glibenclamide had previously been reported to inhibit CFTR. We found that the effects of glibenclamide on the developing pancreas could be mimicked both in vitro and in vivo by GlyH-101.Conclusions/interpretationCollectively, we demonstrate that two small-molecule inhibitors of the CFTR, glibenclamide and GlyH-101, increase the number of pancreatic endocrine cells by increasing the size of the pool of neurogenin 3-positive endocrine progenitors in the developing pancreas.