|ZFIN ID: ZDB-PUB-140815-10|
Whole Organism High Content Screening Identifies Stimulators of Pancreatic Beta-Cell Proliferation
Tsuji, N., Ninov, N., Delawary, M., Osman, S., Roh, A.S., Gut, P., Stainier, D.Y.
|Source:||PLoS One 9: e104112 (Journal)|
|Registered Authors:||Gut, Philipp, Ninov, Nikolay, Stainier, Didier|
|PubMed:||25117518 Full text @ PLoS One|
Tsuji, N., Ninov, N., Delawary, M., Osman, S., Roh, A.S., Gut, P., Stainier, D.Y. (2014) Whole Organism High Content Screening Identifies Stimulators of Pancreatic Beta-Cell Proliferation. PLoS One. 9:e104112.
ABSTRACTInducing 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.