Vascular cells improve functionality of human cardiac organoids

Holly K Voges¹, Simon R Foster², Liam Reynolds², Benjamin L Parker³, Lynn Devilée², Gregory A Quaife-Ryan⁴, Patrick R J Fortuna², Ellen Mathieson², Rebecca Fitzsimmons², Mary Lor², Christopher Batho², Janice Reid⁴, Mark Pocock², Clayton E Friedman⁵, Dalia Mizikovsky⁵, Mathias Francois⁶, Nathan J Palpant⁵, Elise J Needham⁷, Marina Peralta⁸, Gonzalo Del Monte-Nieto⁸, Lynelle K Jones⁹, Ian M Smyth⁹, Neda R Mehdiabadi¹⁰, Francesca Bolk¹⁰, Vaibhao Janbandhu¹¹, Ernestene Yao¹², Richard P Harvey¹³, James J H Chong¹⁴, David A Elliott¹⁵, Edouard G Stanley¹⁵, Sophie Wiszniak¹⁶, Quenten Schwarz¹⁶, David E James¹⁷, Richard J Mills¹, Enzo R Porrello¹⁸, James E Hudson¹⁹

Affiliations

¹ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, School of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
² QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
³ Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney, NSW 2006, Australia; Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia.
⁴ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
⁵ Institute for Molecular Bioscience, University of Queensland, Brisbane 4072, QLD, Australia.
⁶ The Centenary Institute, David Richmond Program for Cardiovascular Research: Gene Regulation and Editing, Sydney Medical School, University of Sydney, Sydney, NSW 2050, Australia.
⁷ Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney, NSW 2006, Australia.
⁸ Australian Regenerative Medicine Institute. Monash University, Clayton, VIC 3800, Australia.
⁹ Department of Anatomy and Developmental Biology, Development and Stem Cells Program, Monash Biomedical Discovery Institute, Monash University, Melbourne, VIC 3800, Australia.
¹⁰ Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
¹¹ Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 2052, Australia.
¹² Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
¹³ Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 2052, Australia; School of Biotechnology and Biomolecular Science, UNSW Sydney, Sydney, NSW 2052, Australia.
¹⁴ Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia; Department of Cardiology, Westmead Hospital, Westmead, NSW 2145, Australia.
¹⁵ Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, School of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
¹⁶ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5001, Australia.
¹⁷ Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney, NSW 2006, Australia; Sydney Medical School, The University of Sydney, Sydney, 2010 NSW, Australia.
¹⁸ Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Melbourne, VIC 3052, Australia. Electronic address: enzo.porrello@mcri.edu.au.
¹⁹ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: james.hudson@qimrberghofer.edu.au.

PMID: 37105170
DOI: 10.1016/j.celrep.2023.112322

Free article

Vascular cells improve functionality of human cardiac organoids

Holly K Voges et al. Cell Rep. 2023.

Free article

. 2023 May 30;42(5):112322.

doi: 10.1016/j.celrep.2023.112322. Epub 2023 Apr 26.

Authors

Affiliations

¹ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, School of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
² QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
³ Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney, NSW 2006, Australia; Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia.
⁴ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.
⁵ Institute for Molecular Bioscience, University of Queensland, Brisbane 4072, QLD, Australia.
⁶ The Centenary Institute, David Richmond Program for Cardiovascular Research: Gene Regulation and Editing, Sydney Medical School, University of Sydney, Sydney, NSW 2050, Australia.
⁷ Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney, NSW 2006, Australia.
⁸ Australian Regenerative Medicine Institute. Monash University, Clayton, VIC 3800, Australia.
⁹ Department of Anatomy and Developmental Biology, Development and Stem Cells Program, Monash Biomedical Discovery Institute, Monash University, Melbourne, VIC 3800, Australia.
¹⁰ Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
¹¹ Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 2052, Australia.
¹² Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
¹³ Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 2052, Australia; School of Biotechnology and Biomolecular Science, UNSW Sydney, Sydney, NSW 2052, Australia.
¹⁴ Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia; Department of Cardiology, Westmead Hospital, Westmead, NSW 2145, Australia.
¹⁵ Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, School of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
¹⁶ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5001, Australia.
¹⁷ Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney, NSW 2006, Australia; Sydney Medical School, The University of Sydney, Sydney, 2010 NSW, Australia.
¹⁸ Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Melbourne, VIC 3052, Australia. Electronic address: enzo.porrello@mcri.edu.au.
¹⁹ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: james.hudson@qimrberghofer.edu.au.

PMID: 37105170
DOI: 10.1016/j.celrep.2023.112322

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: CP: Stem cell research; LAMA5; PDGF; cardiac organoid; disease modeling; endothelial cells; endothelin-1; extracellular matrix; inflammation.

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Conflict of interest statement

Declaration of interests 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.

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Vascular cells improve functionality of human cardiac organoids

Affiliations

Vascular cells improve functionality of human cardiac organoids

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Miscellaneous