Richard J. Mills1, Drew M. Titmarsh1, Xaver Koenig1,2, Benjamin L. Parker3, James G. Ryall4, Gregory A. Quaife-Ryan1, Holly K. Voges1, Mark P. Hodson5,6,7 , Charles Ferguson8, Lauren Drowley9, Alleyn T. Plowright9, Qing-Dong Wang9, Paul Gregorevic10, Mei Xin11, Walter G. Thomas1, Robert G. Parton8,12, Lars K. Nielsen5,6, Bradley S. Launikonis1, David E. James3, David A. Elliott13, Enzo R. Porrello1,*, James E. Hudson1,*

 

1School of Biomedical Sciences, The University of Queensland, St Lucia 4072, Queensland, Australia.
2
Department for Neurophysiology and –pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria
3Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney 2006, NSW, Australia.

4Department of Physiology, The University of Melbourne, Parkville 3010, Victoria, Australia.
5Metabolomics Australia Queensland Node, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia 4072, Queensland, Australia
6Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia 4072, Queensland, Australia.
7School of Pharmacy, The University of Queensland, St Lucia 4072, Queensland, Australia.
8Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Queensland, Australia.
9Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, Sweden
10Baker IDI Heart and Diabetes Institute, Prahran 3004, Victoria, Australia.
11
Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
12Centre for Microscopy and Microanalysis, The University of Queensland, St Lucia 4072, Queensland, Australia.
13Murdoch Children’s Research Institute, Royal Children's Hospital, Parkville 3052, Victoria, Australia; School of Biosciences, The University of Melbourne, Parkville 3052, Victoria, Australia.
*
Co-corresponding authors.

 

Background-The mammalian heart undergoes maturation during postnatal life to meet the increased functional requirements of the adult. However, the key drivers of cardiomyocyte maturation and cell cycle arrest remain poorly defined.

Methods- We developed a 96-well device for functional screening of human cardiac organoids to systematically screen for drivers of maturation and cell cycle arrest. Through interrogation of >10,000 cardiac organoids derived from human pluripotent stem cells, we systematically optimized parameters, including extracellular matrix, metabolic substrate and growth factor conditions that enhance cardiac tissue viability, reproducibility, function and maturation.

Results- Under optimized maturation conditions, functional and molecular characterization revealed that a switch to fatty acid metabolism was a central driver of cardiac maturation. Additionally, under maturation conditions cardiomyocytes were refractory to mitogenic stimuli. We subsequently performed screening using a boutique library of kinase inhibitors and identified a small molecule capable of inducing cardiomyocyte cell cycle re-entry in mature human cardiac tissues and also in the adult mouse heart in vivo.

Conclusions- These studies highlight that human organoids coupled with higher throughput screening platforms have the potential to rapidly expand our knowledge of cardiac biology and potentially unlock novel therapeutic strategies for cardiovascular disease.

 

Corresponding author contact information:

Dr James E. Hudson

School of Biomedical Sciences

The University of Queensland

St Lucia, QLD, 4072, Australia

Tel: +61 7 3365 2957

Email: j.hudson@uq.edu.au

 

Venue

Room: 
AEB Auditorium