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.

AFM nano‐mechanical study of the beating profile of hiPSC‐derived cardiomyocytes beating bodies WT and DM1

“…After few minutes, as shown in Figure 5B, the duration of the single DM1 pulses increased up to 10% over the value at time 0, while the WT BBs evidenced a reduction of the impulse duration of similar magnitude. This is in good agreement with the typical in vivo analyses of the QRS duration in DM1 patients …”

“…This is in good agreement with the typical in vivo analyses of the QRS duration in DM1 patients. 4,10,27 Overall, these results depict the fast response of the cells to the mechanical solicitation and, in addition, suggest that the WT is much more resistant to an external mechanical stress than the DM1. Indeed, for the DM1 BBs, after 90 to 140 minutes of measurements, the single beats change form, hindering a reliable evaluation of the beat duration.…”

“…From a biophysical point of view, the main consequence of the lack of the DMPK gene is a reduction of the strength that the muscular cells can generate, that physiologically speaking has implication in the skeletal development, movement, and cardiac strength . The study of DM1 commonly involves genetic testing or standard animal models, but these approaches are far from ideal due to limits in their application in therapeutic assays . An alternative is the use of isolation of tissue‐specific cells from the patient's small biopsy (striated muscle biopsy).…”

“…3 The study of DM1 commonly involves genetic testing or standard animal models, This article is published in Journal of Molecular Recognition as part of the virtual Special Issue 'AFM BioMed Krakow 2017, edited by Malgorzata Lekka, IFJ PAN, and Pierre Parot, CEA, France, and Jean-Luc Pellequer, IBS, France' but these approaches are far from ideal due to limits in their application in therapeutic assays. 4 An alternative is the use of isolation of tissue-specific cells from the patient's small biopsy (striated muscle biopsy). Recently, several works have presented a tuned reprogramming protocol capable to generate human induced pluripotent stem cells (hiPSCs) starting from several cell types.…”

Duchenne and Becker Muscular Dystrophies: A Review of Animal Models, Clinical End Points, and Biomarker Quantification

“…Kalra et al (2016) suggest that cardiomyocytes derived from iPSCs provide a superior alternative to the mdx mouse to study the cardiac complications of DMD. First, mdx mice develop mild disease late in their lifespan, and mdx mice with a second knockout (double knock out (dko)) that develop cardiac disease earlier have a second gene mutation not present in humans (Kalra et al , 2016).…”