PUBLICATION
Whole Organism High Content Screening Identifies Stimulators of Pancreatic Beta-Cell Proliferation
- Authors
- Tsuji, N., Ninov, N., Delawary, M., Osman, S., Roh, A.S., Gut, P., Stainier, D.Y.
- ID
- ZDB-PUB-140815-10
- 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
Citation
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.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping