Modeling of <i>LMNA</i>-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells
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 <i>LMNA</i> gene encoding the nuclear lamina proteins lamin A and C and without adequate treatment these patients have a poor prognos...
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MDPI AG
2019-06-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/8/6/594 |
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| author | Disheet Shah Laura Virtanen Chandra Prajapati Mostafa Kiamehr Josef Gullmets Gun West Joose Kreutzer Mari Pekkanen-Mattila Tiina Heliö Pasi Kallio Pekka Taimen Katriina Aalto-Setälä |
| author_facet | Disheet Shah Laura Virtanen Chandra Prajapati Mostafa Kiamehr Josef Gullmets Gun West Joose Kreutzer Mari Pekkanen-Mattila Tiina Heliö Pasi Kallio Pekka Taimen Katriina Aalto-Setälä |
| author_sort | Disheet Shah |
| collection | DOAJ |
| description | 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 <i>LMNA</i> 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 <i>LMNA</i>-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 <i>LMNA</i> 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 Ca<sup>2+</sup> dynamics. Taken together, p.S143P hiPSC-CM model mimics hallmarks of <i>LMNA</i>-related DCM and provides a useful tool to study the underlying cellular mechanisms of accelerated cardiac degeneration in this disease. |
| first_indexed | 2024-03-12T06:57:27Z |
| format | Article |
| id | doaj.art-c6fb85b811c545bca8652ab8309eb771 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T06:57:27Z |
| publishDate | 2019-06-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-c6fb85b811c545bca8652ab8309eb7712023-09-02T23:58:38ZengMDPI AGCells2073-44092019-06-018659410.3390/cells8060594cells8060594Modeling of <i>LMNA</i>-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem CellsDisheet Shah0Laura Virtanen1Chandra Prajapati2Mostafa Kiamehr3Josef Gullmets4Gun West5Joose Kreutzer6Mari Pekkanen-Mattila7Tiina Heliö8Pasi Kallio9Pekka Taimen10Katriina Aalto-Setälä11BioMediTech, Faculty of Medicine and Health Technology; Tampere University, 33520 Tampere, FinlandInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandBioMediTech, Faculty of Medicine and Health Technology; Tampere University, 33520 Tampere, FinlandBioMediTech, Faculty of Medicine and Health Technology; Tampere University, 33520 Tampere, FinlandInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandMicro-and Nanosystems Research Group, BioMediTech, Faculty of Medicine and Health Technology, Tampere University, 33140 Tampere, FinlandBioMediTech, Faculty of Medicine and Health Technology; Tampere University, 33520 Tampere, FinlandHelsinki University Hospital, 00029 Helsinki, FinlandMicro-and Nanosystems Research Group, BioMediTech, Faculty of Medicine and Health Technology, Tampere University, 33140 Tampere, FinlandInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandBioMediTech, Faculty of Medicine and Health Technology; Tampere University, 33520 Tampere, FinlandDilated 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 <i>LMNA</i> 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 <i>LMNA</i>-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 <i>LMNA</i> 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 Ca<sup>2+</sup> dynamics. Taken together, p.S143P hiPSC-CM model mimics hallmarks of <i>LMNA</i>-related DCM and provides a useful tool to study the underlying cellular mechanisms of accelerated cardiac degeneration in this disease.https://www.mdpi.com/2073-4409/8/6/594dilated cardiomyopathy<i>LMNA</i>Lamin A/Cinduced pluripotent stem cellhypoxiamicroelectrode array and calcium imaging |
| spellingShingle | Disheet Shah Laura Virtanen Chandra Prajapati Mostafa Kiamehr Josef Gullmets Gun West Joose Kreutzer Mari Pekkanen-Mattila Tiina Heliö Pasi Kallio Pekka Taimen Katriina Aalto-Setälä Modeling of <i>LMNA</i>-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells Cells dilated cardiomyopathy <i>LMNA</i> Lamin A/C induced pluripotent stem cell hypoxia microelectrode array and calcium imaging |
| title | Modeling of <i>LMNA</i>-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells |
| title_full | Modeling of <i>LMNA</i>-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells |
| title_fullStr | Modeling of <i>LMNA</i>-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells |
| title_full_unstemmed | Modeling of <i>LMNA</i>-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells |
| title_short | Modeling of <i>LMNA</i>-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells |
| title_sort | modeling of i lmna i related dilated cardiomyopathy using human induced pluripotent stem cells |
| topic | dilated cardiomyopathy <i>LMNA</i> Lamin A/C induced pluripotent stem cell hypoxia microelectrode array and calcium imaging |
| url | https://www.mdpi.com/2073-4409/8/6/594 |
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