The Organoid Research Laboratory is focussed on developing state-of-the art bioengineering approaches for human 3D organoids. It ultimately aims to use these organoids for discovery of new therapeutics for human disease.
A 96-well platform for the fabrication and culture of 3D cardiac tissues has been recently discovered by the lab.
FIGURE 1: Heart-Dyno platform. A) The 96-well culture inserts with 2 elastic posts that move when the tissue contracts. B) Automated tissue formation in the inserts. C) Contracting cardiac organoid. D) Equations used to approximate force of contraction from post movement. E) Force of contraction and contraction parameter assessment from videos. F) whole-mount immunostaining for screening.
FIGURE 2: Multiple cardiac cell populations spontaneously organise throughout the human cardiac organoids in our Heart-Dyno platform.
Our current programs include understanding the mechanisms of cardiac maturation, interactions between different cell populations in the heart or outside of the heart and the role of metabolism in cardiac biology and function. Our goal is the culture of advanced adult-like muscle in a dish as a model for human cardiac biology, whilst learning about many unknown factors governing heart health.
FIGURE 3: Metabolic changes lead to cell cycle arrest in human cardiac organoids.
Cardiac disease is currently the leading cause of death worldwide, and there are currently more than 22 million people living with heart failure. We are currently using our platforms in house, in collaboration with research partners, and together in industry partnerships for discovery applications to uncover novel therapeutic targets.
FIGURE 4: Adult heart cells are cell cycle arrested and lack the ability to regenerate following injuries such as a heart attack. In this image is the most potent inducer of cardiac cell regeneration we have found in our human cardiac organoids with Compound 6.28.
We are now also extending our technology to other organoid systems, to facilitate similar human 3D tissue models in collaboration with researchers focussed on different tissues and diseases.
Group Leader: James Hudson
- Richard Mills, Postdoctoral Researcher
- Greg Quaife-Ryan, Research Assistant
- Holly Voges, PhD Student
- George Lavers, 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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