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Modeling of LMNA-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 LMNA gene encoding the nuclear lamina proteins lamin A and C and without adequate treatment these patients have a poor prognosis. To get better i...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627421/ https://www.ncbi.nlm.nih.gov/pubmed/31208058 http://dx.doi.org/10.3390/cells8060594 |
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author | Shah, Disheet Virtanen, Laura Prajapati, Chandra Kiamehr, Mostafa Gullmets, Josef West, Gun Kreutzer, Joose Pekkanen-Mattila, Mari Heliö, Tiina Kallio, Pasi Taimen, Pekka Aalto-Setälä, Katriina |
author_facet | Shah, Disheet Virtanen, Laura Prajapati, Chandra Kiamehr, Mostafa Gullmets, Josef West, Gun Kreutzer, Joose Pekkanen-Mattila, Mari Heliö, Tiina Kallio, Pasi Taimen, Pekka Aalto-Setälä, Katriina |
author_sort | Shah, Disheet |
collection | PubMed |
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 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 Ca(2+) 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. |
format | Online Article Text |
id | pubmed-6627421 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-66274212019-07-23 Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells Shah, Disheet Virtanen, Laura Prajapati, Chandra Kiamehr, Mostafa Gullmets, Josef West, Gun Kreutzer, Joose Pekkanen-Mattila, Mari Heliö, Tiina Kallio, Pasi Taimen, Pekka Aalto-Setälä, Katriina Cells Article 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 Ca(2+) 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. MDPI 2019-06-15 /pmc/articles/PMC6627421/ /pubmed/31208058 http://dx.doi.org/10.3390/cells8060594 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Shah, Disheet Virtanen, Laura Prajapati, Chandra Kiamehr, Mostafa Gullmets, Josef West, Gun Kreutzer, Joose Pekkanen-Mattila, Mari Heliö, Tiina Kallio, Pasi Taimen, Pekka Aalto-Setälä, Katriina Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells |
title | Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells |
title_full | Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells |
title_fullStr | Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells |
title_full_unstemmed | Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells |
title_short | Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells |
title_sort | modeling of lmna-related dilated cardiomyopathy using human induced pluripotent stem cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627421/ https://www.ncbi.nlm.nih.gov/pubmed/31208058 http://dx.doi.org/10.3390/cells8060594 |
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