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

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http://hdl.handle.net/10138/305157

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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 2019 , ' Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells ' , Cells , vol. 8 , no. 6 , 594 . https://doi.org/10.3390/cells8060594

Title: Modeling of LMNA-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells
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
Contributor: University of Helsinki, HUS Heart and Lung Center
Date: 2019-06
Language: eng
Number of pages: 21
Belongs to series: Cells
ISSN: 2073-4409
URI: http://hdl.handle.net/10138/305157
Abstract: 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 beta -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.
Subject: dilated cardiomyopathy
LMNA
Lamin A
C
induced pluripotent stem cell
hypoxia
microelectrode array and calcium imaging
TO-BEAT VARIABILITY
SARCOPLASMIC-RETICULUM
VENTRICULAR MYOCYTES
HEART-FAILURE
MUTATION
GENE
REPOLARIZATION
STIMULATION
EXPRESSION
HYPOXIA
1182 Biochemistry, cell and molecular biology
3111 Biomedicine
3121 Internal medicine
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