PuSH - Publikationsserver des Helmholtz Zentrums München: Whole organism high content screening identifies stimulators of pancreatic beta-cell proliferation.

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Tsuji, N.* ; Ninov, N.* ; Delawary, M.* ; Osman, S.* ; Roh, A.S.* ; Gut, P.* ; Stainier, D.Y.*

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

PLoS ONE 9:e104112 (2014)

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Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.

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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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