Whole organism high content screening identifies stimulators of pancreatic beta-cell proliferation

• Published in: PloS one 2014-08, Vol.9 (8), p.e104112
• Main Authors: Tsuji, Naoki, Ninov, Nikolay, Delawary, Mina, Osman, Sahar, Roh, Alex S, Gut, Philipp, Stainier, Didier Y R
• Format: Article
• Language: English
• Subjects: Acids; Adenosine; Animals; Animals, Genetically Modified; Beta cells; Biochemistry; Biology; Biology and Life Sciences; Biophysics; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Danio rerio; Diabetes; Diabetes mellitus; Drug Evaluation, Preclinical; Fluorescence; Glucocorticoids; High-Throughput Screening Assays; Homeostasis; Hyperglycemia; Insulin resistance; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Kinases; Medical screening; Medicine; Medicine and Health Sciences; Metabolism; Modulators; Pancreas; Reagents; Regeneration; Regeneration - drug effects; Research and Analysis Methods; Retinoic acid; Serotonin; Signaling; Small Molecule Libraries; Stem cells; Stimulators; Trazodone - pharmacology; Tretinoin - pharmacology; Ubiquitin; Ubiquitination - drug effects; Zebrafish
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0104112

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.