Whole organism high content screening identifies stimulators of pancreatic beta-cell proliferation.
Whole organism high content screening identifies stimulators of pancreatic beta-cell proliferation.
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DOI：
10.1371/journal.pone.0104112
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Stainier DY
中科院分区：
文献类型：
--
作者：
Tsuji N;Ninov N;Delawary M;Osman S;Roh AS;Gut P;Stainier DY
在糖尿病患者中诱导β细胞团扩增以恢复葡萄糖稳态是一种有前途的治疗策略。尽管已经进行了几项体外研究以鉴定β细胞群扩增的调节剂，但尚未实现体内恢复内源性β细胞群。为了识别体内β细胞复制的潜在刺激因子，我们建立了转基因斑马鱼系，该转基因斑马鱼系通过使用基于荧光泛素化的细胞周期指示剂（FUCCI）技术来监测和量化细胞增殖。使用这些新试剂，我们进行了无偏倚的化学筛选，并确定了20种显着增加体内β细胞增殖的小分子。重要的是，这些结构不同的分子，包括临床批准的药物，调节三种特定的信号通路：血清素，视黄酸和糖皮质激素，显示了我们筛选的高灵敏度和鲁棒性。值得注意的是，两类药物，视黄酸和糖皮质激素，也促进β细胞消融后的β细胞再生。因此，本研究建立了用于体内β细胞增殖的高通量小分子筛选的原理证明，并鉴定了刺激β细胞增殖和再生的化合物。
Inducing beta-cell mass expansion in diabetic patients with the aim to restore glucose homeostasis is a promising therapeutic strategy. Although several in vitro studies have been carried out to identify modulators of beta-cell mass expansion, restoring endogenous beta-cell mass in vivo has yet to be achieved. To identify potential stimulators of beta-cell replication in vivo, we established transgenic zebrafish lines that monitor and allow the quantification of cell proliferation by using the fluorescent ubiquitylation-based cell cycle indicator (FUCCI) technology. Using these new reagents, we performed an unbiased chemical screen, and identified 20 small molecules that markedly increased beta-cell proliferation in vivo. Importantly, these structurally distinct molecules, which include clinically-approved drugs, modulate three specific signaling pathways: serotonin, retinoic acid and glucocorticoids, showing the high sensitivity and robustness of our screen. Notably, two drug classes, retinoic acid and glucocorticoids, also promoted beta-cell regeneration after beta-cell ablation. Thus, this study establishes a proof of principle for a high-throughput small molecule-screen for beta-cell proliferation in vivo, and identified compounds that stimulate beta-cell proliferation and regeneration.
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影响因子：
7.7
作者：
Ohta Y;Kosaka Y;Kishimoto N;Wang J;Smith SB;Honig G;Kim H;Gasa RM;Neubauer N;Liou A;Tecott LH;Deneris ES;German MS
通讯作者：
German MS
影响因子：
2.7
作者：
Jurczyk A;Roy N;Bajwa R;Gut P;Lipson K;Yang C;Covassin L;Racki WJ;Rossini AA;Phillips N;Stainier DY;Greiner DL;Brehm MA;Bortell R;diIorio P
通讯作者：
diIorio P
影响因子：
14.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Sakaue-Sawano, Asako;Kurokawa, Hiroshi;Miyawaki, Atsushi
通讯作者：
Miyawaki, Atsushi
影响因子：
4.8
作者：
Ng, Ka Yan;Ma, Man Ting;Leung, Po Sing
通讯作者：
Leung, Po Sing