Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), and is characterized by progressive weakness in skeletal and cardiac muscles. Currently, dilated cardiomyopathy due to cardiac muscle loss is one of the major causes of lethality in late-stage DMD patients. To study the molecular mechanisms underlying dilated cardiomyopathy in DMD heart, we generated cardiomyocytes (CMs) from DMD and healthy control induced pluripotent stem cells (iPSCs). DMD iPSC-derived CMs (iPSC-CMs) displayed dystrophin deficiency, as well as the elevated levels of resting Ca2+, mitochondrial damage and cell apoptosis. Additionally, we found an activated mitochondria-mediated signaling network underlying the enhanced apoptosis in DMD iPSC-CMs. Furthermore, when we treated DMD iPSC-CMs with the membrane sealant Poloxamer 188, it significantly decreased the resting cytosolic Ca2+ level, repressed caspase-3 (CASP3) activation and consequently suppressed apoptosis in DMD iPSC-CMs. Taken together, using DMD patient-derived iPSC-CMs, we established an in vitro model that manifests the major phenotypes of dilated cardiomyopathy in DMD patients, and uncovered a potential new disease mechanism. Our model could be used for the mechanistic study of human muscular dystrophy, as well as future preclinical testing of novel therapeutic compounds for dilated cardiomyopathy in DMD patients.

Human iPSC-derived cardiomyocytes and tissue engineering strategies for disease modeling and drug screening

“…Similarly, Lin and colleagues demonstrated that cardiomyocytes derived from DMD patient iPSCs exhibited characteristic dystrophin deficiency, as well as elevated levels of resting Ca 2+ , mitochondrial damage and cell apoptosis. Additionally, they demonstrated that treatment with the membrane sealant Poloxamer 188 significantly decreased resting cytosolic Ca 2+ levels, repressed caspase-3 (CASP3) activation and consequently suppressed apoptosis in these cells (Lin et al, 2015). …”

Translation of Human-Induced Pluripotent Stem Cells

“…Since the groundbreaking creation of the first human iPSCs (9), many groups have applied this technology to model human diseases, with amyotrophic lateral sclerosis and various congenital diseases among the first to be modeled using patient-specific iPSCs (12,50,51). Following these reports, many have attempted to study human diseases using iPSCs from patients suffering from neurodegenerative diseases (50,52), cardiovascular disorders (53–56), muscular dystrophies (57,58), and hematologic disorders (59,60), to name a few. Cardiovascular diseases that have been studied are summarized in Table 1.…”

Induced pluripotent stem cells for modeling neurological disorders

“…Modeling DMD in vitro will help disclose the neurological mechanism of this disease and even allow to correct the dystrophin deficit in the muscle. To date, cardiomyoblast cells, muscle cells and neurons have been generated from iPSC cells [79][80][81][82] . The first group to reprogram cells from DMD patients was Park et al [66] in 2008, followed by other groups modeling DMD in vitro and whose primary objective was to correct the dystrophin in muscle cells.…”