title: Can Human Pluripotent Stem Cell-Derived Cardiomyocytes Advance Understanding of Muscular Dystrophies?
abstract: Muscular dystrophies (MDs) are clinically and molecularly a highly heterogeneous group of single-gene disorders that primarily affect striated muscles. Cardiac disease is present in several MDs where it is an important contributor to morbidity and mortality. Careful monitoring of cardiac issues is necessary but current management of cardiac involvement does not effectively protect from disease progression and cardiac failure. There is a critical need to gain new knowledge on the diverse molecular underpinnings of cardiac disease in MDs in order to guide cardiac treatment development and assist in reaching a clearer consensus on cardiac disease management in the clinic. Animal models are available for the majority of MDs and have been invaluable tools in probing disease mechanisms and in pre-clinical screens. However, there are recognized genetic, physiological, and structural differences between human and animal hearts that impact disease progression, manifestation, and response to pharmacological interventions. Therefore, there is a need to develop parallel human systems to model cardiac disease in MDs. This review discusses the current status of cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSC) to model cardiac disease, with a focus on Duchenne muscular dystrophy (DMD) and myotonic dystrophy (DM1). We seek to provide a balanced view of opportunities and limitations offered by this system in elucidating disease mechanisms pertinent to human cardiac physiology and as a platform for treatment development or refinement.
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, UK.
authors.forename: Spandan
authors.initials: S
authors.lastname: Kalra
authors.affiliation: Dubowitz Neuromuscular Centre, Department of Molecular Neurosciences, University College London - Institute of Child Health, London, UK.
authors.forename: Federica
authors.initials: F
authors.lastname: Montanaro
authors.affiliation: Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Denning
mesh_terms: D006331:Heart Diseases / Q000209:etiology / Q000503:physiopathology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008955:Models, Cardiovascular; D009136:Muscular Dystrophies / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000166:cytology*; D009223:Myotonic Dystrophy / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D039904:Pluripotent Stem Cells
keywords: Cas9/CRISPR genome editing; Duchenne muscular dystrophy (DMD); Human embryonic stem cells; cardiomyocytes; disease modelling; exon skipping; gene therapy; human induced pluripotent stem cells; myotonic dystrophy (DM1)