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Updated: Apr 25, 2026
A High-content In Vitro Pancreatic Islet β-cell Replication Discovery Platform
Published on: July 16, 2016
Whole organism high content screening identifies stimulators of pancreatic beta-cell proliferation
Naoki Tsuji1, Nikolay Ninov2, Mina Delawary1
1Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, the Diabetes Center, Institute for Regeneration Medicine and Liver Center, University of California San Francisco, San Francisco, California, United States of America.
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.
Insights
Researchers screened for compounds that increase beta-cell mass in vivo. They identified 20 small molecules, including drugs targeting serotonin, retinoic acid, and glucocorticoids, that stimulate beta-cell proliferation and regeneration.
Area of Science:
- Endocrinology
- Regenerative Medicine
- Pharmacology
Background:
- Restoring beta-cell mass is a key strategy for managing diabetes.
- In vitro studies identified beta-cell mass modulators, but in vivo restoration remains a challenge.
Purpose of the Study:
- To develop and validate a high-throughput screening method for identifying in vivo beta-cell proliferation stimulators.
- To discover novel small molecules that promote endogenous beta-cell mass expansion and regeneration.
Main Methods:
- Established transgenic zebrafish lines utilizing fluorescent ubiquitylation-based cell cycle indicator (FUCCI) technology to monitor beta-cell proliferation.
- Performed an unbiased chemical screen of small molecules in vivo.
- Assessed the impact of identified compounds on beta-cell regeneration following ablation.
Main Results:
- Identified 20 small molecules that significantly increase beta-cell proliferation in vivo.
- These molecules are structurally diverse and modulate serotonin, retinoic acid, and glucocorticoid signaling pathways.
- Retinoic acid and glucocorticoid classes also enhanced beta-cell regeneration post-ablation.
Conclusions:
- Demonstrated the feasibility of high-throughput in vivo screening for beta-cell proliferation.
- Identified specific compounds and pathways that stimulate beta-cell proliferation and regeneration, offering therapeutic potential for diabetes.
