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Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy.
Dis Model Mech. 2015 May; 8(5):457-66.DM

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 Ca(2+), 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 Ca(2+) 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.

Authors+Show Affiliations

Department of Developmental Biology, University of Pittsburgh School of Medicine, 530 45th Street, 8117 Rangos Research Center, Pittsburgh, PA 15201, USA.Department of Developmental Biology, University of Pittsburgh School of Medicine, 530 45th Street, 8117 Rangos Research Center, Pittsburgh, PA 15201, USA.Department of Developmental Biology, University of Pittsburgh School of Medicine, 530 45th Street, 8117 Rangos Research Center, Pittsburgh, PA 15201, USA.Center for Cellular and Systems Electrophysiology, Departments of Physiology and Biophysics, SUNY, Buffalo, NY 14214, USA.Department of Developmental Biology, University of Pittsburgh School of Medicine, 530 45th Street, 8117 Rangos Research Center, Pittsburgh, PA 15201, USA.Department of Stem Cells, Tissue Engineering & Modelling (STEM), University of Nottingham, Nottingham, NG7 2RD, UK.Departments of Obstetrics and Gynecology, and Physiology and Biophysics, SUNY, Buffalo, NY 14214, USA.Center for Cellular and Systems Electrophysiology, Departments of Physiology and Biophysics, SUNY, Buffalo, NY 14214, USA.Department of Stem Cells, Tissue Engineering & Modelling (STEM), University of Nottingham, Nottingham, NG7 2RD, UK.Department of Developmental Biology, University of Pittsburgh School of Medicine, 530 45th Street, 8117 Rangos Research Center, Pittsburgh, PA 15201, USA lyang@pitt.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25791035

Citation

Lin, Bo, et al. "Modeling and Study of the Mechanism of Dilated Cardiomyopathy Using Induced Pluripotent Stem Cells Derived From Individuals With Duchenne Muscular Dystrophy." Disease Models & Mechanisms, vol. 8, no. 5, 2015, pp. 457-66.
Lin B, Li Y, Han L, et al. Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy. Dis Model Mech. 2015;8(5):457-66.
Lin, B., Li, Y., Han, L., Kaplan, A. D., Ao, Y., Kalra, S., Bett, G. C., Rasmusson, R. L., Denning, C., & Yang, L. (2015). Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy. Disease Models & Mechanisms, 8(5), 457-66. https://doi.org/10.1242/dmm.019505
Lin B, et al. Modeling and Study of the Mechanism of Dilated Cardiomyopathy Using Induced Pluripotent Stem Cells Derived From Individuals With Duchenne Muscular Dystrophy. Dis Model Mech. 2015;8(5):457-66. PubMed PMID: 25791035.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy. AU - Lin,Bo, AU - Li,Yang, AU - Han,Lu, AU - Kaplan,Aaron D, AU - Ao,Ying, AU - Kalra,Spandan, AU - Bett,Glenna C L, AU - Rasmusson,Randall L, AU - Denning,Chris, AU - Yang,Lei, Y1 - 2015/03/19/ PY - 2014/12/11/received PY - 2015/03/16/accepted PY - 2015/3/21/entrez PY - 2015/3/21/pubmed PY - 2016/3/2/medline KW - Dilated cardiomyopathy KW - Duchenne muscular dystrophy KW - Induced pluripotent stem cells SP - 457 EP - 66 JF - Disease models & mechanisms JO - Dis Model Mech VL - 8 IS - 5 N2 - 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 Ca(2+), 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 Ca(2+) 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. SN - 1754-8411 UR - https://www.unboundmedicine.com/medline/citation/25791035/Modeling_and_study_of_the_mechanism_of_dilated_cardiomyopathy_using_induced_pluripotent_stem_cells_derived_from_individuals_with_Duchenne_muscular_dystrophy_ L2 - http://dmm.biologists.org/cgi/pmidlookup?view=long&pmid=25791035 DB - PRIME DP - Unbound Medicine ER -