Stem Cell Medicine

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Heart Disorders

MCRI Stem Cell Medicine's research on heart disorders is headed by Associate Professor Enzo Porrello and Dr David Elliott. This research program uses patient-matched stem cells to grow mini hearts (organoids) to understand the causes of childhood heart disease, find treatments, and eventually develop replacement organs.

Research Summary

Heart disease is the leading cause of death in infants, affecting up to 1 in 100 live births. Complex forms of congenital heart disease (CHD) often require multiple surgical interventions during early childhood. Surgical advances over the past 20 years have dramatically increased survival rates, with more than 85% of children now surviving into adulthood. As a result, CHD is now considered a life-long disease. However, an emerging and alarming trend in recent years has been the sharp rise in number of children with complex CHD hospitalised due to heart failure, a condition that can only be resolved by heart transplantation. As a result, there are increasing numbers of children on mechanical assist support requiring heart transplantation. The cost of treating childhood failure is growing, with the annual total inpatient cost for heart failure in Australian paediatric hospitals estimated to be $120 million. Current treatment options are clearly inadequate and new approaches to radically change patient trajectories are needed.

At MCRI, our researchers are world leaders in generating models of the heart from patient stem cells. By recreating human heart tissue from stem cells, we are now able to ‘model’ the human organ in the laboratory. As these stem cells can be made from patients, it is now possible to precisely investigate the cause of childhood heart disease in each specific patient.  The hope is to use these mini-hearts to better understand heart development and diseases, to test drugs for results and toxicity to find treatments for CHD, and eventually to bioengineer heart tissues for transplantation during surgery.

Projects

Modelling heart disease in a dish using patient-derived stem cells and drug screening

One key area of our heart research focuses on creating stem cells from patients with congenital heart disease and recreating their heart tissue in our laboratories.  This allows us to recreate and study their disease more closely – this method of research is called disease modelling.  If we are able to determine a genetic cause for the disease through studying a patient’s tissue in the laboratory, we now have the gene editing capability and technology to correct mutations found in that patients’ genome.  By comparing a patient’s genetically mutated and corrected cell lines, we are able to better understand a disease’s cause and progression, which informs our understanding of any potential preventative measures, tests for that disease, developing new treatments and hopefully cures. We are also investigating whether mini-hearts can be used to screen for drugs that cause damage to heart tissue, or relieve the underlying causes of heart disease. 

Creating an artificial pump using patient-derived stem cells to treat childhood heart disease

Single ventricle defects, also referred to as single ventricle physiology, are a group of CHD defects whereby only one of the heart’s ventricles functions correctly. Right and left ventricle defects exist, with the altered physiologies severely affecting the entire circulatory system. Single ventricle patients require at least three major surgeries in the first few years of life leading to the Fontan circulation. The circulation is named after the final and definitive surgery performed, the Fontan operation, whereby the inferior vena cava is surgically connected to the pulmonary artery using a Gore-tex conduit. Following this procedure, desaturated blood travels independently of the pumping heart from the body directly to the lungs, thus improving oxygen delivery to the single ventricle heart. However, this is clearly a palliative solution. To date, few studies have explored the potential for stem cells in the setting of childhood heart disease. By combining stem cell technologies with state-of-the-art bioengineering strategieas, this project aims to create an artificial pump using patient-derived stem cells to support heart function in children with single ventricle physiology. The artificial pump derived from the patient’s own stem cells would be implanted either during or after the Fontan operation and would help to prevent heart failure in this population of single ventricle patients.

Understanding how the newborn heart develops and regenerates following injury

In contrast to adults, we have discovered that neonates are able to regenerate their heart tissue following damage, for example caused by a heart attack. If we were able to understand the mechanisms that drive heart regeneration in the newborn and that lead to loss of regenerative capacity in adults, we may be able to harness this regenerative potential therapeutically for heart repair. We are using stem cells to create mini-hearts (organoids) that can be used to model key aspects of human heart development including regeneration and maturation. We are also investigating whether mini-hearts can be used to screen for drugs that can stimulate heart muscle cells to divide and regenerate heart tissue following a heart attack.

Publications

Anderson DJ ... Harvey RP, Oshlack A, Cheung MM, Mummery CL, Petrou S, Elefanty AG, Stanley EG, Elliott DA. (2018) NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network. Nat Commun. 9(1):1373.

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

Voges HK, Mills RJ, Elliott DA, Parton RG, Porrello ER#, Hudson JE*. (2017) Development of a human cardiac organoid model reveals innate regenerative potentialDevelopment. 144(6):1118-1127. *Co-corresponding. 

Mills RJ ... Elliott DA, Porrello ER, Hudson JE. (2017) Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrestProc Natl Acad Sci U S A. 114(40):E8372-E81.

Phelan DG, Anderson DJ, Howden SE, ... Petrou S, Elefanty AG, Stanley EG, James PA, Macciocca I, Bahlo M, Cheung MM, Amor DJ, Elliott DA*, Lockhart PJ. (2016) ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy. Eur Heart J. 37(33):2586-90. *Senior Author

Skelton RJ, Costa M, A ...Ng ES, Elefanty AG, Stanley EG, Pouton CW, Haynes JM, Ardehali R, Davis RP, Mummery CL, Elliott DA. (2014) SIRPA, VCAM1 and CD34 identify discrete lineages during early human cardiovascular development. Stem Cell Res. 13(1):172-9. 

Porrello ER, Mahmoud AI, Simpson E, Hill JA Richardson JA, Olson EN, Sadek H. (2011) Transient regenerative potential of the neonatal mouse heartScience. 331(6020): 1078-80. 

Elliott DA ... Haynes JM, Pouton CW, Kaye DM, Mummery CL, Elefanty AG, Stanley EG. (2011) NKX2-5(eGFP/w) hESCs for isolation of human cardiac progenitors and cardiomyocytes. Nat Methods. 8(12):1037-40. 

  

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  • CardioRegen: is an integrated clinical and research program across the Melbourne Children’s Campus and Parkville Precinct.