Muscle Bioengineering
Our laboratory uses stem cells to generate human bioengineered muscle, both skeletal muscle and heart muscle.
This enables ‘disease in a dish’ studies that allow us to understand how muscle is perturbed due to genetic or environmental disorders. These ‘mini-muscles’ act and function like the muscle in your body, giving us the unique ability to measure important properties like muscle strength.
As we can generate 1000s of mini-muscles, it provides unprecedented access to human tissue for cell biology, and disease modelling studies. Using this approach, we aim to gain insight into childhood myopathies in order to develop new therapies.
Video: Cardiac organoids (heart muscle) beating in a dish.
Video: Bioengineered skeletal muscle contracting and producing force in a dish.
Group Leaders
Group Members
Our projects
Facioscapulohumeral muscular dystrophy therapeutic target discovery
Facioscapulohumeral muscular dystrophy (FSHD) is a disorder characterized by weakness and wasting of muscles in the face, shoulder blades, and upper arms. The most probable cause of FSHD is genetic inheritance, which leads to the aberrant expression of the double homeobox protein 4 gene (DUX4).
FSHD can be recapitulated in bioengineered muscle via over-expression DUX4. Engineered muscle over-expressing DUX4, showed marked weakness ( approximately 85 per cent decrease in strength) and perturbation of metabolic and mitochondrial function as early events following activation of DUX transcription factors.
By manipulating the perturbed pathways, we will investigate whether the DUX4-induced functional decline can be rescued. Collaboration with A/Professor Paul Gregorevic and Dr Kevin Watt
Gene editing therapy platform for Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by out-of-frame mutations in the DMD gene, which occurs in one out of 5,000 male births. DMD codes for dystrophin, a protein that supports muscle fibre strength. Our aim is to improve patients’ quality of life by developing a CRISPR-Cas-based therapy for local restoration of dystrophin expression.
In this project, we aim to demonstrate that the platform is safe and effective in bioengineered muscle, mouse, and rat models. Collaboration with Professor Niels Geijsen
Modelling skeletal muscle aging (sarcopenia)
Preliminary data shows that bioengineered skeletal muscle generated from older donor muscle stem cells (approximately 70 years old) have decreased strength compared to younger donors (approximately 25 years old). This project will investigate the interplay between exercise and ageing, using a multi-omic approach, to uncover novel mechanistic insights and potential therapeutic targets for age-related muscle weakness in humans. Collaboration with A/Professor Andy Philp
Advanced maturation of bioengineered muscle
In general, stem-cell-derived systems are more representative of neonatal tissue rather than adult, limiting their applicability. We aim to develop approaches to accelerate bioengineered muscle maturation to adult-like tissue and demonstrate their utility.
Funding
- National Health and Medical Research Council (NHMRC)
- reNEW Center for Stem Cell Medicine
Collaborations
- A/Professor Andy Philp
- Dr Peter Houweling
- Dr Kevin Watt
- Dr Sean Humphries
- Professor James Hudson
- Professor Enzo Porrello
- A/Professor David Elliot
- Dr Ben Parker
- A/Professor Paul Gregorevic
- Professor Niels Geijsen
Featured publications
Mills, R.J., et al., Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest. PNAS (2017) 114(40): 8372-81.
Mills, R.J., et al., Drug screening in human PSC-cardiac organoids identifies pro-proliferative compounds acting via the mevalonate pathway. Cell Stem Cell (2019) 24(6):895-907.e6.
Mills, R.J., et al., Development of a human skeletal micro muscle platform with pacing capabilities. Biomaterials (2019) 198:217-227.
Mills, R.J., et al., BET Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV-2 Infection. Cell (2021) 184(8).
Mills, R.J., et al., Neurturin is a PGC-1α1-controlled myokine that promotes motor neuron recruitment and neuromuscular junction formation. Molecular Metabolism (2018) 7:12-22.