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Article

Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells

1
BioMediTech, Faculty of Medicine and Health Technology; Tampere University, 33520 Tampere, Finland
2
Institute of Biomedicine, University of Turku, 20520 Turku, Finland
3
Turku Doctoral Programme of Molecular Medicine, University of Turku, 20520 Turku, Finland
4
Micro-and Nanosystems Research Group, BioMediTech, Faculty of Medicine and Health Technology, Tampere University, 33140 Tampere, Finland
5
Helsinki University Hospital, 00029 Helsinki, Finland
6
Department of Pathology, Turku University Hospital, 20520 Turku, Finland
7
Medical School, University of Tampere, 33520 Tampere, Finland
8
Heart Hospital, Tampere University Hospital, 33520 Tampere, Finland
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Shared last author.
Cells 2019, 8(6), 594; https://doi.org/10.3390/cells8060594
Received: 30 April 2019 / Revised: 12 June 2019 / Accepted: 13 June 2019 / Published: 15 June 2019
(This article belongs to the Special Issue iPS Cells for Disease Modeling)
Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure and heart transplantation. A portion of familial DCM is due to mutations in the LMNA gene encoding the nuclear lamina proteins lamin A and C and without adequate treatment these patients have a poor prognosis. To get better insights into pathobiology behind this disease, we focused on modeling LMNA-related DCM using human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM). Primary skin fibroblasts from DCM patients carrying the most prevalent Finnish founder mutation (p.S143P) in LMNA were reprogrammed into hiPSCs and further differentiated into cardiomyocytes (CMs). The cellular structure, functionality as well as gene and protein expression were assessed in detail. While mutant hiPSC-CMs presented virtually normal sarcomere structure under normoxia, dramatic sarcomere damage and an increased sensitivity to cellular stress was observed after hypoxia. A detailed electrophysiological evaluation revealed bradyarrhythmia and increased occurrence of arrhythmias in mutant hiPSC-CMs on β-adrenergic stimulation. Mutant hiPSC-CMs also showed increased sensitivity to hypoxia on microelectrode array and altered Ca2+ dynamics. Taken together, p.S143P hiPSC-CM model mimics hallmarks of LMNA-related DCM and provides a useful tool to study the underlying cellular mechanisms of accelerated cardiac degeneration in this disease. View Full-Text
Keywords: dilated cardiomyopathy; LMNA; Lamin A/C; induced pluripotent stem cell; hypoxia; microelectrode array and calcium imaging dilated cardiomyopathy; LMNA; Lamin A/C; induced pluripotent stem cell; hypoxia; microelectrode array and calcium imaging
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MDPI and ACS Style

Shah, D.; Virtanen, L.; Prajapati, C.; Kiamehr, M.; Gullmets, J.; West, G.; Kreutzer, J.; Pekkanen-Mattila, M.; Heliö, T.; Kallio, P.; Taimen, P.; Aalto-Setälä, K. Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells. Cells 2019, 8, 594. https://doi.org/10.3390/cells8060594

AMA Style

Shah D, Virtanen L, Prajapati C, Kiamehr M, Gullmets J, West G, Kreutzer J, Pekkanen-Mattila M, Heliö T, Kallio P, Taimen P, Aalto-Setälä K. Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells. Cells. 2019; 8(6):594. https://doi.org/10.3390/cells8060594

Chicago/Turabian Style

Shah, Disheet, Laura Virtanen, Chandra Prajapati, Mostafa Kiamehr, Josef Gullmets, Gun West, Joose Kreutzer, Mari Pekkanen-Mattila, Tiina Heliö, Pasi Kallio, Pekka Taimen, and Katriina Aalto-Setälä. 2019. "Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells" Cells 8, no. 6: 594. https://doi.org/10.3390/cells8060594

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