@article{54c1c9cc62bc43a983425c1d4cb1de59,
title = "Vascular cells improve functionality of human cardiac organoids",
abstract = "Crosstalk between cardiac cells is critical for heart performance. Here we show that vascular cells within human cardiac organoids (hCOs) enhance their maturation, force of contraction, and utility in disease modeling. Herein we optimize our protocol to generate vascular populations in addition to epicardial, fibroblast, and cardiomyocyte cells that self-organize into in-vivo-like structures in hCOs. We identify mechanisms of communication between endothelial cells, pericytes, fibroblasts, and cardiomyocytes that ultimately contribute to cardiac organoid maturation. In particular, (1) endothelial-derived LAMA5 regulates expression of mature sarcomeric proteins and contractility, and (2) paracrine platelet-derived growth factor receptor β (PDGFRβ) signaling from vascular cells upregulates matrix deposition to augment hCO contractile force. Finally, we demonstrate that vascular cells determine the magnitude of diastolic dysfunction caused by inflammatory factors and identify a paracrine role of endothelin driving dysfunction. Together this study highlights the importance and role of vascular cells in organoid models.",
keywords = "cardiac organoid, CP: Stem cell research, disease modeling, endothelial cells, endothelin-1, extracellular matrix, inflammation, LAMA5, PDGF",
author = "Voges, {Holly K.} and Simon Foster and Reynolds, {Liam T.} and Parker, {Benjamin L} and Lynn Devilee and Quaife-Ryan, {Gregory A.} and Fortuna, {Patrick R.J.} and Ellen Mathieson and Rebecca Fitzsimmons and Mary Lor and Christopher Batho and Janice Reid and Mark Pocock and Friedmand, {Clayton E.} and Dalia Mizikovsky and Mathias Francois and Palpant, {Nathan J.} and Needham, {Elise J.} and Marina Peralta and {del Monte Nieto}, Gonzalo and Jones, {Lynelle K.} and Smyth, {Ian M.} and Mehdiabadi, {Neda R.} and Francesca Bolk and Vaibhao Janbandhu and Ernestene Yao and Harvey, {Richard P.} and Chong, {James J.H.} and Elliott, {David A.} and Stanley, {Edouard G.} and Sophie Wiszniak and Quenten Schwarz and James, {David E.} and Mills, {Richard J.} and Porrello, {Enzo R.} and Hudson, {James E.}",
note = "Funding Information: We acknowledge grant and fellowship support from the National Health and Medical Research Council of Australia (R.P.H., E.R.P., and J.E.H.), Heart Foundation of Australia (G.d.M.-N., J.J.H.C., E.R.P., and J.E.H.), QIMR Berghofer Medical Research Institute (J.E.H.), The Stafford Fox Foundation (E.R.P.), the Royal Children's Hospital Foundation (E.R.P.), Foundation Leducq Transatlantic Network of Excellence in Cardiovascular Research (R.P.H. and V.J.), Australian Research Council Strategic Initiative in Stem Cell Science (Stem Cells Australia) (R.P.H., V.J., E.R.P., and J.E.H.), and the Victor Chang Cardiac Research Institute Innovation Centre (funded by the New South Wales Government Ministry of Health ) and Queensland Health (J.E.H.). The Novo Nordisk Foundation Center for Stem Cell Medicine (R.J.M., E.R.P., D.A.E., and E.G.S.) is supported by Novo Nordisk Foundation grants ( NNF21CC0073729 ). The Murdoch Children{\textquoteright}s Research Institute is supported by the Victorian Government{\textquoteright}s Operational Infrastructure Support Program . Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. J.E.H. is supported by a Snow Medical Fellowship . Funding Information: We used the Australian National Fabrication Facility Queensland Node for the fabrication of the Heart-Dyno molds. WTC CRISPRi GCaMP hiPSCs (Karyotype: 46, XY; RRID CVCL_VM38) generously provided by M. Mandegar and B. Conklin (UCSF, Gladstone Institute). We thank Grace Chojnowski and Michael Rist for FACS at QIMR Berghofer and Geoff Osborne and Virginia Nink for FACS at The University of Queensland. Microscopy was aided by Tam Nguyen and Nigel Waterhouse at QIMR Berghofer and Carsten Minten and Taryn Gulnan from Leica. We acknowledge grant and fellowship support from the National Health and Medical Research Council of Australia (R.P.H. E.R.P. and J.E.H.), Heart Foundation of Australia (G.d.M.-N. J.J.H.C. E.R.P. and J.E.H.), QIMR Berghofer Medical Research Institute (J.E.H.), The Stafford Fox Foundation (E.R.P.), the Royal Children's Hospital Foundation (E.R.P.), Foundation Leducq Transatlantic Network of Excellence in Cardiovascular Research (R.P.H. and V.J.), Australian Research Council Strategic Initiative in Stem Cell Science (Stem Cells Australia) (R.P.H. V.J. E.R.P. and J.E.H.), and the Victor Chang Cardiac Research Institute Innovation Centre (funded by the New South Wales Government Ministry of Health) and Queensland Health (J.E.H.). The Novo Nordisk Foundation Center for Stem Cell Medicine (R.J.M. E.R.P. D.A.E. and E.G.S.) is supported by Novo Nordisk Foundation grants (NNF21CC0073729). The Murdoch Children's Research Institute is supported by the Victorian Government's Operational Infrastructure Support Program. Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. J.E.H. is supported by a Snow Medical Fellowship. H.K.V. R.J.M. E.R.P. and J.E.H. designed the experiment(s). D.A.E. L.J. I.S. C.E.F. N.P. and E.S. provided reagents. H.K.V. S.R.F. L.D. L.R. G.A.Q.-R. V.J. E.Y. M.L. C.B. R.F. M.P. S.W. P.F. E.M. S.R.F. B.L.P. E.N. and J.E.H. conducted experiments. H.K.V. S.R.F. L.R. L.D. R.P.H. V.J. N.R.M. G.A.Q.-R. J.J.H.C. M.F. F.B. G.d.M.-N. I.S. Q.S. N.P. D.E.J. R.J.M. E.R.P. and J.E.H. analyzed the results. H.K.V. E.R.P. and J.E.H. wrote the manuscript. All authors reviewed and approved the manuscript. R.J.M. J.E.H. G.A.Q.-R. and E.R.P. are listed as co-inventors on pending patents that relate to cardiac organoid maturation and cardiac regeneration therapeutics. E.R.P. and J.E.H. are listed as co-inventors on pending patents that relate to endothelial cells in 3D cardiac products. J.E.H. is a co-inventor on licensed patents relating to engineered heart muscle. R.J.M. E.R.P. and J.E.H. are co-founders, scientific advisors, and stockholders in Dynomics. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = may,
day = "30",
doi = "10.1016/j.celrep.2023.112322",
language = "English",
volume = "42",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier",
number = "5",
}
