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.
Date: 2014
Source: PLoS One 9: e104112 (Journal)
Registered Authors: Gut, Philipp, Ninov, Nikolay, Stainier, Didier
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cell Cycle/drug effects
  • Cell Proliferation/drug effects
  • Drug Evaluation, Preclinical*
  • High-Throughput Screening Assays
  • Insulin-Secreting Cells/drug effects*
  • Insulin-Secreting Cells/metabolism*
  • Regeneration/drug effects
  • Small Molecule Libraries
  • Trazodone/pharmacology
  • Tretinoin/pharmacology
  • Ubiquitination/drug effects
  • Zebrafish
PubMed: 25117518 Full text @ PLoS One
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ABSTRACT
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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