The Cardiac Bioengineering Laboratory is focused on developing and using state-of-the art bioengineering approaches to understand how the heart works. Ultimately we aim to use this information to develop new therapeutics for human heart disease to enhance heart performance.
In our laboratory we use Nobel Prize winning technology discovered by Shinya Yamanaka to turn cells derived from skin or blood biopsies into human pluripotent stem cells. These are not to be confused with other stem cell types and are a distinct type of stem cell – where pluripotent means they can turn into any cell type in the body and stem cell means we can grow them indefinitely in the lab. This means we can produce potentially unlimited numbers of difficult to obtain (eg. heart or brain) human cells in the lab.
In some cases, human pluripotent stem cell derived heart cells fail to model disease due to their “immature” state. In order to overcome this issue, we have developed technology to generate more mature 3D bioengineered cardiac tissues. We have also extended this technology to develop the tissues in scalable formats for studies requiring higher throughput read-outs including screening and drug discovery. Our Heart-Dyno device is capable of automatically forming tissues in a 96-well plate platform – 96 human heart muscle tissues in something the size of a mobile phone. Custom software developed in our lab enables us to automatically assess multiple functional readouts from these tissues including force of contraction, rate, activation/relaxation kinetics and beat-to-beat variability. All of these parameters are important when assessing the function of heart tissue and make it possible to screen how different conditions alter heart function.
Over many years we have shown that non-cardiomyocyte cell types are essential to make functional 3D heart tissues. Accordingly, we have developed a unique human pluripotent stem cell differentiation protocol that yields not only cardiomyocytes, but also progenitor cells that give rise to fibroblasts, pericytes, endothelial cells and epicardial cells, all of which self-organize within the tissues – hence we call the tissues human cardiac organoids (hCO).
While we understand a lot about biology, there is still a lot to discover. Even for well-studied processes such as phosphorylation we currently only understand the purpose of ~5% of the phosphorylation sites on the proteins. Our current research program is focused on understanding how the heart works. If we can understand the molecular biology underlying how the heart works together with what goes wrong in disease, we can identify new therapeutic targets to enhance heart performance and eventually turn these into therapeutics. Using these principles we have discovered 2 new therapeutic candidates for heart failure we are currently developing in pre-clinical work and will continue to build this pipeline over time.
Group Leader: James Hudson
- Dr Richard Mills, Postdoctoral Researcher
- Liam Reynolds, Research Assistant
- Greg Quaife-Ryan, Research Assistant
- Mark Pocock, PhD Student
- Marta Orlowska, PhD Student
- Chris Batho, PhD Student
- 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. PNAS 2017 114(40):E8372-E8381.
- Engineered cardiac muscle can be used to promote the structural and functional maturation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). However, previous studies have not yet produced cardiac tissues with metabolic and proliferative maturation.
- We develop a 96-well screening platform and screen for cardiac maturation conditions in engineered cardiac muscle. We found that simulating the postnatal switch in metabolic substrates from carbohydrates to fatty acids promoted a switch in metabolism, DNA damage response, and cell cycle arrest in hPSC-CM.
- Using our platform we identify a potent pro-regenerative small molecule.
- 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 136(12): 1123–1139.
- We currently do not fully understand why the adult heart loses its regenerative capacity.
- A transcriptional resource of multiple cardiac cell populations including cardiomyocytes, fibroblasts, endothelial cells, and leukocytes in the neonatal and adult heart with and without myocardial infarction.
- Identification of several developmentally regulated and injury-responsive transcriptional networks associated with neonatal regenerative and adult fibrotic responses to injury.
- Adult cardiomyocytes and endothelial cells do not reactivate a neonatal proliferative program following myocardial infarction.
- Detection of epigenetic modifications associated with loss of regenerative capacity including chromatin compaction around cell cycle genes during postnatal cardiomyocyte maturation.
- 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.
- It is unknown whether humans have a regenerative capacity in early life similar to other mammals such as rodents, but some clinical case reports suggest this may be the case.
- We developed an injury model in engineered human cardiac tissues.
- Following injury the engineered human cardiac tissues displayed an innate regenerative capacity.
- Tiburcy M, Hudson JE, Balfanz P, Schlick S, Meyer T, Liao M-LC, Levent E, Raad F, Zeidler S, Wingender E, Riegler J, Wang M, Gold JD, Kehat I, Wettwer E, Ravens U, Dierickx P, van Laake LW, Goumans MJ, Khadjeh S, Toischer K, Hasenfuss G, Couture LA, Unger A, Linke WA, Araki T, Neel B, Keller G, Gepstein L, Wu JC, Zimmermann W-H. Defined Engineered Human Myocardium with Advanced Maturation for Applications in Heart Failure Modelling and Repair. Circulation 2017 135(19):1832-1847.
- Proof-of-concept for the engineering of scalable force-generating human myocardium from a variety of human pluripotent stem cells and biopsy-derived fibroblasts under defined, serum-free conditions.
- Evidence for morphological, molecular, and functional maturation beyond the present state-of-the-art is demonstrated (eg, positive force-frequency response, sarcomere assembly with robust M-band formation).
- Simulation of a human heart failure phenotype in the dish with (1) contractile dysfunction, (2) loss of a positive force-frequency response, (3) adrenergic signal desensitization, (4) cardiomyocyte hypertrophy, and (5) biomarker release (N-terminal pro B-type natriuretic peptide) by chronic catecholamine stimulation.
- Implantability of scalable engineered human myocardium patches is demonstrated.
- Hudson JE, Brooke G, Blair C, Wolvetang EJ, Cooper-White JJ. Development of Myocardial Constructs Using Modulus-Matched Acrylated Polypropylene Glycol Triol (aPPGT) Substrate and Different Non-Myocyte Cell Populations. Tissue Engineering Part A 2011 17(17-18):2279-89.
- Use of a new elastic polymer for cardiac tissue engineering applications.
- The polymer can be implanted onto the heart in vivo with no adverse side-effects.
- Cardiac tissues require a stromal population, and the stromal population type can influence the tissue properties.
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