Advances in Stem Cell Modeling of Dystrophin-Associated Disease: Implications for the Wider World of Dilated Cardiomyopathy

Abstract

Familial dilated cardiomyopathy (DCM) is mostly caused by mutations in genes encoding cytoskeletal and sarcomeric proteins. In the pediatric population, DCM is the predominant type of primitive myocardial disease. A severe form of DCM is associated with mutations in the DMD gene encoding dystrophin, which are the cause of Duchenne Muscular Dystrophy (DMD). DMD-associated cardiomyopathy is still poorly understood and orphan of a specific therapy. In the last 5 years, a rise of interest in disease models using human induced pluripotent stem cells (hiPSCs) has led to more than 50 original studies on DCM models. In this review paper, we provide a comprehensive overview on the advances in DMD cardiomyopathy disease modeling and highlight the most remarkable findings obtained from cardiomyocytes differentiated from hiPSCs of DMD patients. We will also describe how hiPSCs based studies have contributed to the identification of specific myocardial disease mechanisms that may be relevant in the pathogenesis of DCM, representing novel potential therapeutic targets.

Role of the Renin-Angiotensin-Aldosterone System in Dystrophin-Deficient Cardiomyopathy

“…The discovery of these cells has led to create in vitro DDC models mimicking the histological, molecular and clinical characteristics observed in the human disease. Thus, iPSCs offer an accurate tool to study human DDC progression and screening or develop potential therapeutic approaches [188][189][190].…”

The harder the climb the better the view: The impact of substrate stiffness on cardiomyocyte fate

“…Dystrophin binds both actin and β-dystroglycan, connecting the transmembrane components of the DGC to the cytoskeleton. Therefore, dystrophin and DGC deficiency impairs striated muscle integrity and leads to contraction-induced damage [59,60]. Notably, mutations in the genes encoding many proteins are strictly related to dilated cardiomyopathy [60].…”

“…Therefore, dystrophin and DGC deficiency impairs striated muscle integrity and leads to contraction-induced damage [59,60]. Notably, mutations in the genes encoding many proteins are strictly related to dilated cardiomyopathy [60]. The second complex present at cardiac muscle costameres is the integrin-vinculin-talin complex [11,15,61].…”

“…In this context, hiPSC-CMs obtained from patients are the most suitable platform for the investigation of earlystage defects related to the onset of many cardiomyopathies. To this aim, the possibility of targeting genes of interest by CRISPR-Cas9 gene editing technology allows the validation of the pathogenicity of any cardiomyopathy-associated variant [60,122]. Moreover, it may contribute to elucidate the role of specific proteins with debated function and involved in physiological responses during cECM stiffening.…”

Role of the Renin–Angiotensin–Aldosterone System in Dystrophin-Deficient Cardiomyopathy

“…The discovery of these cells has led to create in vitro DDC models mimicking the histological, molecular and clinical characteristics observed in the human disease. Thus, iPSCs offer an accurate tool to study human DDC progression and screening or develop potential therapeutic approaches [ 188 , 189 , 190 ].…”