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

N Tsuji, N Ninov, M Delawary, S Osman, AS Roh… - PloS one, 2014 - journals.plos.org
N Tsuji, N Ninov, M Delawary, S Osman, AS Roh, P Gut, DYR Stainier
PloS one, 2014journals.plos.org
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 …
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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