title: Whole organism high content screening identifies stimulators of pancreatic beta-cell proliferation.
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.
authors.affiliation: Department 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.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tsuji
authors.affiliation: Department 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; Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; DFG Research Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany; Paul Langerhans Institute Dresden, German Center for Diabetes Research, Dresden, Germany.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Ninov
authors.affiliation: Department 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.
authors.forename: Mina
authors.initials: M
authors.lastname: Delawary
authors.affiliation: Department 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.
authors.forename: Sahar
authors.initials: S
authors.lastname: Osman
authors.affiliation: Department 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.
authors.forename: Alex S
authors.initials: AS
authors.lastname: Roh
authors.affiliation: Department 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.
authors.forename: Philipp
authors.initials: P
authors.lastname: Gut
authors.affiliation: Department 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; Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects; D054852:Small Molecule Libraries; D014196:Trazodone / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects; D015027:Zebrafish
chemical_list: D054852:Small Molecule Libraries; D014212:Tretinoin; D014196:Trazodone