Cardiac Bioengineering

The Cardiac Bioengineering Laboratory aims to develop state-of-the art bioengineering approaches for human myocardium. The team uses our screening platforms in house, in collaboration with research partners, and together in industry partnerships for a variety of different discovery science and therapeutics development applications. These include understanding the mechanisms of cardiac maturation, interactions between different cell populations in the heart, the role of metabolism in maturation and regeneration and development of new therapeutics for patients to prevent heart failure.

CURRENT RESEARCH

  • heart in a computer to identify new heart failure therapeutics (Richard Mills, PhD)
  • discovery of regenerative therapeutics using human cardiac organoids (Richard Mills, PhD)
  • discovery of regenerative therapeutics using transcriptional profiling (Gregory Quaife-Ryan, PhD)
  • metabolic mechanisms causing diastolic dysfunction (James Krycer, PhD)
  • preventing pro-inflammatory factor-driven cardiac dysfunction (Mary Lor & Simon Foster, PhD)
  • mechanisms of metabolism (mevalonate) in cardiac regeneration (Christopher Batho, PhD candidate)
  • circadian regulation of heart muscle biology and function (Marta Orlowska, PhD candidate)
  • metabolic dysregulation in RYR2 calcium leak (Mark Pocock, PhD candidate)
  • mechanistic basis for the evolutionary loss of cardiac regeneration (Lynn Devilee, PhD candidate)
  • bioengineering human heart muscle for children with heart defects (Liam Reynolds)

Staff

  • Dr Richard Mills, PhD
  • Dr Liam Reynolds
  • Mark Pocock
  • Lynn Devilee
  • Marta Orlowska
  • Dr James Krycer
  • Christopher Batho
  • Dr Gregory Quaife-Ryan
  • Dr Mary Lor
  • Dr Simon Foster

Internal Collaborators

External Collaborators

  • Associate Professor Enzo Porrello, Murdoch Children’s Research Institute
  • Dr David Elliott, Murdoch Children’s Research Institute
  • Professor David James, The University of Sydney
  • Associate Professor James Chong, The University of Sydney
  • Professor Richard Harvey, Victor Change Cardiac Research Institute
  • Dr Gonzalo del Monte Nieto, Monash University
  • Dr Ben Parker, University of Melbourne
  • Associate Professor Paul Gregorevic, University of Melbourne
  • Associate Professor Eddy Kizana, Westmead Institute for Medical Research
  • Professor Lea Delbridge, University of Melbourne
  • Dr Ian Smyth, Monash University
  • Dr John O’Sullivan, University of Sydney
  • Associate Professor Andrew Murphy, Baker Institute
  • Associate Professor Mat Francois, Centenary Institute
  • Professor Walter Thomas, University of Queensland
  • Dr Nathan Palpant, University of Queensland
  • Associate Professor Brad Launikonis, University of Queensland
  • Associate Professor Dominic Ng, University of Queensland
  • Associate Mirana Ramialison, Monash University
  • Professor Chris Semsarian, Centenary Institute
  • Professor Julie McGaughran, Genetics Health Queensland
  • Professor Rob Parton, University of Queensland
  • Dr Brian Tse, Translational Research Institute
  • Dr John Atherton, Royal Brisbane & Women’s Hospital
  • Dr Michael Cheung, The Royal Children’s Hospital
  • Professor Christian Brizard, The Royal Children’s Hospital
  • Professor Igor Konstantinov, The Royal Children’s Hospital
  • Dr Qing-Dong Wang, AstraZeneca, Sweden
  • Dr Cathy Wilson, University of Cambridge
  • Dr Chas Hong, University of Maryland
  • Professor Christine Mummery, Leiden University
  • Max Kelsen
  • Dynomics
  • Snow Medical Fellowship 2021-2028
  • Australian Genomics Cardiovascular Genetic Disorders Flagship Functional Genomics Platform 2020-2021
  • MRFF 2020 Rapid Screening of Approved Drugs in Stem Cell Models for COVID-19 Treatment 2020-2021
  • Metcalf Prize- National Stem Cell Foundation of Australia 2020
  • NHMRC Project Grant (CIB) APP1160256 2019-2022
  • MRFF Accelerated Research – Stem Cells Grant Funding 2019-2020
  • National Heart Foundation Future Leaders Fellowship L1 2017-2020
  • NHMRC Career Development Fellowship L1 APP1122883 2017-2020

Mills RJ, Parker BL, Quaife-Ryan GA, Voges HK, Needham EJ, Bornot A, Ding M, Andersson H, Polla M, Elliott DA, Drowley L, Clausen M, Plowright AT, Barrett IP, Wang Q-D, James DE, Porrello ER*, Hudson JE*. Drug Screening in Human PSC-Cardiac Organoids Identifies Pro-Proliferative Compounds Acting via the Mevalonate Pathway. Cell Stem Cell 2019 24(6):895-907. *Co-corresponding author

A major reason why we do not have cardiac regeneration therapeutics is because we lack a mature heart model with the capacity for screening. In collaboration with AstraZeneca we used human cardiac organoids to discover new drug candidates for cardiac regeneration. This led to IP PCT/AU2019/050238 for ‘Cardiac Regeneration’ and we are now working together in partnership to translate these findings. This work led to my 2019 Tall Poppy Award and the Metcalf Prize for Stem Cell Research.

Mills RJ, Titmarsh DM, Koenig X, Parker BL, Ryall JG, Quaife-Ryan GA, Voges HK, Hodson MP, Ferguson C, Drowley L, Plowright AT, Needham EJ, Wang Q-D, Gregorevic P, Xin M, Thomas WG, Parton RG, Nielsen LK, Launikonis BS, James DE, Elliott DA, Porrello ER*, Hudson JE*. Functional Screening in Human Cardiac Organoids Reveals a Metabolic Mechanism for Cardiomyocyte Cell Cycle Arrest. Proceedings of the National Academy of Sciences USA 2017 114(40):E8372-E8381. *Co-corresponding author

Development of a high throughput 96 well plate human cardiac organoid platform for screening. Screening in over 10,000 human cardiac organoids led to conditions to promote maturation including metabolic maturation and cell cycle arrest. This led to IP WO2018035574A1 for ‘Mature Human Cardiac Organoids’ and a partnership with AstraZeneca. Mechanistic insight also revealed pathways driving proliferation and a new lead compound for cardiac regeneration. Together this led to my 2017 Centenary Institute Medical Innovation Award.

Quaife-Ryan GA, Sim CB, Ziemann M, Kaspi A, Rafehi H, Ramialison M, El-Osta A, Hudson JE*, Porrello ER*. Multi-Cellular Transcriptional Analysis of Mammalian Heart Regeneration. Circulation 2017 136(12): 1123–1139. *Co-corresponding author

There is a profound maturation phase in mammalian hearts during the first week of life postnatally, including loss of regenerative capacity. We profiled the major cell populations in mouse hearts during postnatal development and following injury. We established a publically available resource for the cardiovascular community (https://www.stemformatics.org/datasets/search?ds_id=7241&filter=Mus%20musculus). This insight led to studies of multiple metabolic pathways for both maturation (Pub 2 above) and regeneration (Pub 1 above). Greg who conducted this work, won best PhD publication prize from the Australian Physiological Society in 2017 and from the International Society for Heart Research Australasian Chapter in 2018.

Voges HK, Mills RJ, Elliott DA, Parton RG, Porrello ER*, Hudson JE*. Innate Regenerative Potential of Immature Human Heart Tissue. Development 2017 144(6):1118-1127. *Co-corresponding author

Development of a cardiac regeneration model in human cardiac organoids. We demonstrated that: 1) immature human cardiac tissue has a regenerative capacity similar to that of other mammals (only at a foetal/neonatal stage), and 2) immature mammalian hearts are developmentally “primed” for regeneration – they are already transcriptionally ready for proliferation rather than induction of a specific injury response. This concept was confirmed in Pubs 1,2,3 above. Holly who carried out this work won best ECR paper from Stem Cells Australia in 2017 for the resulting publication.

Mills RJ, Parker BL, Monnot P, Needham EJ, Vivien CJ, Ferguson C, Parton RG, James DE, Porrello ER*, Hudson JE*. Development of a human skeletal micro muscle platform with pacing capabilities. Biomaterials 2019 198:217-227. *Co-corresponding author

Development and optimization of miniaturised human skeletal muscle for screening applications. Enables precise interrogation of skeletal muscle under paced conditions including the identification of factors that improve skeletal muscle function and paracrine interactions.