Tags

Type your tag names separated by a space and hit enter

Electrophysiological abnormalities in induced pluripotent stem cell-derived cardiomyocytes generated from Duchenne muscular dystrophy patients.
J Cell Mol Med. 2019 03; 23(3):2125-2135.JC

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle degenerative disease, caused by mutations in the dystrophin gene and resulting in death because of respiratory or cardiac failure. To investigate the cardiac cellular manifestation of DMD, we generated induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (iPSC-CMs) from two DMD patients: a male and female manifesting heterozygous carrier. Dystrophin mRNA and protein expression were analysed by qRT-PCR, RNAseq, Western blot and immunofluorescence staining. For comprehensive electrophysiological analysis, current and voltage clamp were used to record transmembrane action potentials and ion currents, respectively. Microelectrode array was used to record extracellular electrograms. X-inactive specific transcript (XIST) and dystrophin expression analyses revealed that female iPSCs underwent X chromosome reactivation (XCR) or erosion of X chromosome inactivation, which was maintained in female iPSC-CMs displaying mixed X chromosome expression of wild type (WT) and mutated alleles. Both DMD female and male iPSC-CMs presented low spontaneous firing rate, arrhythmias and prolonged action potential duration. DMD female iPSC-CMs displayed increased beat rate variability (BRV). DMD male iPSC-CMs manifested decreased If density, and DMD female and male iPSC-CMs showed increased ICa,L density. Our findings demonstrate cellular mechanisms underlying electrophysiological abnormalities and cardiac arrhythmias in DMD.

Authors+Show Affiliations

Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. Department of Biotechnology, Technion - Israel Institute of Technology, Haifa, Israel.Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.Victor Babes National Institute of Pathology, Bucharest, Romania.Health in Code, Corunna, Spain.Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

Pub Type(s)

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

Language

eng

PubMed ID

30618214

Citation

Eisen, Binyamin, et al. "Electrophysiological Abnormalities in Induced Pluripotent Stem Cell-derived Cardiomyocytes Generated From Duchenne Muscular Dystrophy Patients." Journal of Cellular and Molecular Medicine, vol. 23, no. 3, 2019, pp. 2125-2135.
Eisen B, Ben Jehuda R, Cuttitta AJ, et al. Electrophysiological abnormalities in induced pluripotent stem cell-derived cardiomyocytes generated from Duchenne muscular dystrophy patients. J Cell Mol Med. 2019;23(3):2125-2135.
Eisen, B., Ben Jehuda, R., Cuttitta, A. J., Mekies, L. N., Shemer, Y., Baskin, P., Reiter, I., Willi, L., Freimark, D., Gherghiceanu, M., Monserrat, L., Scherr, M., Hilfiker-Kleiner, D., Arad, M., Michele, D. E., & Binah, O. (2019). Electrophysiological abnormalities in induced pluripotent stem cell-derived cardiomyocytes generated from Duchenne muscular dystrophy patients. Journal of Cellular and Molecular Medicine, 23(3), 2125-2135. https://doi.org/10.1111/jcmm.14124
Eisen B, et al. Electrophysiological Abnormalities in Induced Pluripotent Stem Cell-derived Cardiomyocytes Generated From Duchenne Muscular Dystrophy Patients. J Cell Mol Med. 2019;23(3):2125-2135. PubMed PMID: 30618214.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Electrophysiological abnormalities in induced pluripotent stem cell-derived cardiomyocytes generated from Duchenne muscular dystrophy patients. AU - Eisen,Binyamin, AU - Ben Jehuda,Ronen, AU - Cuttitta,Ashley J, AU - Mekies,Lucy N, AU - Shemer,Yuval, AU - Baskin,Polina, AU - Reiter,Irina, AU - Willi,Lubna, AU - Freimark,Dov, AU - Gherghiceanu,Mihaela, AU - Monserrat,Lorenzo, AU - Scherr,Michaela, AU - Hilfiker-Kleiner,Denise, AU - Arad,Michael, AU - Michele,Daniel E, AU - Binah,Ofer, Y1 - 2019/01/08/ PY - 2018/10/07/received PY - 2018/12/02/revised PY - 2018/12/05/accepted PY - 2019/1/9/pubmed PY - 2020/7/8/medline PY - 2019/1/9/entrez KW - Duchenne muscular dystrophy KW - X chromosome inactivation KW - arrhythmia KW - dilated cardiomyopathy KW - induced pluripotent stem cell-derived cardiomyocytes SP - 2125 EP - 2135 JF - Journal of cellular and molecular medicine JO - J. Cell. Mol. Med. VL - 23 IS - 3 N2 - Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle degenerative disease, caused by mutations in the dystrophin gene and resulting in death because of respiratory or cardiac failure. To investigate the cardiac cellular manifestation of DMD, we generated induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (iPSC-CMs) from two DMD patients: a male and female manifesting heterozygous carrier. Dystrophin mRNA and protein expression were analysed by qRT-PCR, RNAseq, Western blot and immunofluorescence staining. For comprehensive electrophysiological analysis, current and voltage clamp were used to record transmembrane action potentials and ion currents, respectively. Microelectrode array was used to record extracellular electrograms. X-inactive specific transcript (XIST) and dystrophin expression analyses revealed that female iPSCs underwent X chromosome reactivation (XCR) or erosion of X chromosome inactivation, which was maintained in female iPSC-CMs displaying mixed X chromosome expression of wild type (WT) and mutated alleles. Both DMD female and male iPSC-CMs presented low spontaneous firing rate, arrhythmias and prolonged action potential duration. DMD female iPSC-CMs displayed increased beat rate variability (BRV). DMD male iPSC-CMs manifested decreased If density, and DMD female and male iPSC-CMs showed increased ICa,L density. Our findings demonstrate cellular mechanisms underlying electrophysiological abnormalities and cardiac arrhythmias in DMD. SN - 1582-4934 UR - https://www.unboundmedicine.com/medline/citation/30618214/Electrophysiological_abnormalities_in_induced_pluripotent_stem_cell_derived_cardiomyocytes_generated_from_Duchenne_muscular_dystrophy_patients_ L2 - https://doi.org/10.1111/jcmm.14124 DB - PRIME DP - Unbound Medicine ER -