Journal article
Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest
RJ Mills, DM Titmarsh, X Koenig, BL Parker, JG Ryall, GA Quaife-Ryan, HK Voges, MP Hodson, C Ferguson, L Drowley, AT Plowright, EJ Needham, QD Wang, P Gregorevic, M Xin, WG Thomas, RG Parton, LK Nielsen, BS Launikonis, DE James Show all
Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2017
Abstract
The mammalian heart undergoes maturation during postnatal life to meet the increased functional requirements of an adult. However, the key drivers of this process remain poorly defined. We are currently unable to recapitulate postnatal maturation in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), limiting their potential as a model system to discover regenerative therapeutics. Here, we provide a summary of our studies, where we developed a 96-well device for functional screening in human pluripotent stem cell-derived cardiac organoids (hCOs). Through interrogation of >10,000 organoids, we systematically optimize parameters, including extracellular matrix (ECM), metabolic subst..
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Grants
Awarded by National Heart, Lung, and Blood Institute
Funding Acknowledgements
We thank Shaun Walters for his assistance in setting up the customized Leica DMI8 microscope for our applications and Dr. Sean Lal (Sydney Heart Bank) for providing the human heart biopsy for proteomic analysis. We thank the Developmental Studies Hybridoma Bank for providing the beta-catenin (PY489) and titin antibodies. We used the Australian National Fabrication Facility Queensland Node for the fabrication of the Heart-Dyno molds. We also thank QFAB bioinformatics for access to MetaCore as well as the GVL project and the Research Computing Centre for access to the Galaxyqld server (https://galaxy-qld.genome.edu.au/galaxy). We acknowledge the use of the Australian Microscopy & Microanalysis Research Facility at the Center for Microscopy and Microanalysis at The University of Queensland. R.G.P. was supported by National Health and Medical Research Council of Australia Grants APP1037320, APP1058565, and APP569542 and the Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology. D.A.E. and E.R.P. are supported by the Victorian Government's Operational Infrastructure Support Program. E.R.P. and J.E.H. are supported by fellowships and project grants from the National Health and Medical Research Council, the National Heart Foundation, Stem Cells Australia, and The University of Queensland.