Modeling and Studying Mechanism of Dilated Cardiomyopathy Using Induced Pluripotent Stem Cells Derived From Duchenne Muscular Dystrophy (DMD) Patients

نویسندگان

  • Bo Lin
  • Yang Li
  • Lu Han
  • Aaron D. Kaplan
  • Ying Ao
  • Spandan Kalra
  • Glenna CL Bett
  • Randall L Rasmusson
  • Chris Denning
  • Lei Yang
چکیده

Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), and characterized by progressive weakness in skeletal and cardiac muscles. Currently, dilated cardiomyopathy due to cardiac muscle loss, becomes one of the major lethal causes of 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 (iPS) cells. DMD iPS cell-derived CMs (iPSC-CMs) displayed dystrophin deficiency, as well as the elevated levels of resting calcium, mitochondrial damage and cell apoptosis. Additionally, we found an activated mitochondriamediated signaling network underlying the enhanced apoptosis in DMD iPSC-CMs. Furthermore, we treated DMD iPSC-CMs with a membrane sealant Poloxamer 188, which significantly decreased the resting cytosolic calcium level, repressed CASP3 activation and consequently suppressed apoptosis in DMD iPSC-CMs. Altogether, using DMD patientderived iPSC-CMs, we established an in vitro model to manifest the major phenotypes of dilated cardiomyopathy in DMD patients, and uncovered a potential novel disease mechanism. Our study benefits mechanistic study of human muscular dystrophy, as well as the future preclinical testing of novel therapeutic compounds for dilated cardiomyopathy in DMD patients.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

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

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 cardiomy...

متن کامل

Dmm019505 457..466

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), and is characterized by progressive weakness inskeletal andcardiacmuscles.Currently, dilatedcardiomyopathydue 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...

متن کامل

CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice

Duchenne muscular dystrophy (DMD), caused by mutations in the X-linked dystrophin gene (DMD), is characterized by fatal degeneration of striated muscles. Dilated cardiomyopathy is one of the most common lethal features of the disease. We deployed Cpf1, a unique class 2 CRISPR (clustered regularly interspaced short palindromic repeats) effector, to correct DMD mutations in patient-derived induce...

متن کامل

Early pathogenesis of Duchenne muscular dystrophy modelled in patient-derived human induced pluripotent stem cells

Duchenne muscular dystrophy (DMD) is a progressive and fatal muscle degenerating disease caused by a dystrophin deficiency. Effective suppression of the primary pathology observed in DMD is critical for treatment. Patient-derived human induced pluripotent stem cells (hiPSCs) are a promising tool for drug discovery. Here, we report an in vitro evaluation system for a DMD therapy using hiPSCs tha...

متن کامل

Concordant but Varied Phenotypes among Duchenne Muscular Dystrophy Patient-Specific Myoblasts Derived using a Human iPSC-Based Model.

Duchenne muscular dystrophy (DMD) remains an intractable genetic disease. Althogh there are several animal models of DMD, there is no human cell model that carries patient-specific DYSTROPHIN mutations. Here, we present a human DMD model using human induced pluripotent stem cells (hiPSCs). Our model reveals concordant disease-related phenotypes with patient-dependent variation, which are partia...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:

دوره   شماره 

صفحات  -

تاریخ انتشار 2015