دورية أكاديمية
Drug Screening in Human PSC-Cardiac Organoids Identifies Pro-proliferative Compounds Acting via the Mevalonate Pathway.
| العنوان: | Drug Screening in Human PSC-Cardiac Organoids Identifies Pro-proliferative Compounds Acting via the Mevalonate Pathway. |
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| المؤلفون: | Mills RJ; School of Biomedical Sciences, The University of Queensland, St Lucia 4072, QLD, Australia; Centre for Cardiac and Vascular Biology, The University of Queensland, St Lucia 4072, QLD, Australia; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Parker BL; Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney 2006, NSW, Australia., Quaife-Ryan GA; School of Biomedical Sciences, The University of Queensland, St Lucia 4072, QLD, Australia; Centre for Cardiac and Vascular Biology, The University of Queensland, St Lucia 4072, QLD, Australia; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Voges HK; School of Biomedical Sciences, The University of Queensland, St Lucia 4072, QLD, Australia; Centre for Cardiac and Vascular Biology, The University of Queensland, St Lucia 4072, QLD, Australia; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Needham EJ; Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney 2006, NSW, Australia., Bornot A; Discovery Sciences, IMED Biotech Unit, AstraZeneca Cambridge, Cambridge, UK., Ding M; Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Gothenburg, Sweden., Andersson H; Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Gothenburg, Sweden., Polla M; Medicinal Chemistry, Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, Gothenburg, Sweden., Elliott DA; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville 3052, VIC, Australia., Drowley L; Bioscience Heart Failure, Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, Gothenburg, Sweden., Clausen M; Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Gothenburg, Sweden., Plowright AT; Medicinal Chemistry, Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, Gothenburg, Sweden., Barrett IP; Discovery Sciences, IMED Biotech Unit, AstraZeneca Cambridge, Cambridge, UK., Wang QD; Bioscience Heart Failure, Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca Gothenburg, Gothenburg, Sweden., James DE; Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney 2006, NSW, Australia., Porrello ER; School of Biomedical Sciences, The University of Queensland, St Lucia 4072, QLD, Australia; Centre for Cardiac and Vascular Biology, The University of Queensland, St Lucia 4072, QLD, Australia; Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville 3052, VIC, Australia; Department of Physiology, School of Biomedical Sciences, The University of Melbourne, Parkville 3010, VIC, Australia. Electronic address: enzo.porrello@mcri.edu.au., Hudson JE; School of Biomedical Sciences, The University of Queensland, St Lucia 4072, QLD, Australia; Centre for Cardiac and Vascular Biology, The University of Queensland, St Lucia 4072, QLD, Australia; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia. Electronic address: james.hudson@qimrberghofer.edu.au. |
| المصدر: | Cell stem cell [Cell Stem Cell] 2019 Jun 06; Vol. 24 (6), pp. 895-907.e6. Date of Electronic Publication: 2019 Mar 28. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 101311472 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1875-9777 (Electronic) Linking ISSN: 18759777 NLM ISO Abbreviation: Cell Stem Cell Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Cambridge, MA : Cell Press |
| مواضيع طبية MeSH: | Drug Evaluation, Preclinical/*methods , Mevalonic Acid/*metabolism , Myocardium/*cytology , Myocytes, Cardiac/*physiology , Organoids/*cytology, Cell Cycle ; Cell Proliferation ; Cells, Cultured ; High-Throughput Screening Assays ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Myocytes, Cardiac/drug effects ; Organ Culture Techniques ; Proteomics ; Regeneration ; Signal Transduction |
| مستخلص: | We have previously developed a high-throughput bioengineered human cardiac organoid (hCO) platform, which provides functional contractile tissue with biological properties similar to native heart tissue, including mature, cell-cycle-arrested cardiomyocytes. In this study, we perform functional screening of 105 small molecules with pro-regenerative potential. Our findings reveal surprising discordance between our hCO system and traditional 2D assays. In addition, functional analyses uncovered detrimental effects of many hit compounds. Two pro-proliferative small molecules without detrimental impacts on cardiac function were identified. High-throughput proteomics in hCO revealed synergistic activation of the mevalonate pathway and a cell-cycle network by the pro-proliferative compounds. Cell-cycle reentry in hCO and in vivo required the mevalonate pathway as inhibition of the mevalonate pathway with a statin attenuated pro-proliferative effects. This study highlights the utility of human cardiac organoids for pro-regenerative drug development, including identification of underlying biological mechanisms and minimization of adverse side effects. (Copyright © 2019 Elsevier Inc. All rights reserved.) |
| التعليقات: | Comment in: Cell Stem Cell. 2019 Jun 6;24(6):833-834. (PMID: 31173709) |
| فهرسة مساهمة: | Keywords: cardiomyocyte proliferation; cholesterol; drug development; organoid; pluripotent stem cells; statin |
| المشرفين على المادة: | 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) S5UOB36OCZ (Mevalonic Acid) |
| تواريخ الأحداث: | Date Created: 20190402 Date Completed: 20200721 Latest Revision: 20200721 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1016/j.stem.2019.03.009 |
| PMID: | 30930147 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1875-9777 |
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| DOI: | 10.1016/j.stem.2019.03.009 |