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Phenotypic Variability in iPSC-Induced Cardiomyocytes and Cardiac Fibroblasts Carrying Diverse LMNA Mutations

Mutations in the LMNA gene (encoding lamin A/C) are a significant cause of familial arrhythmogenic cardiomyopathy. Although the penetrance is high, there is considerable phenotypic variability in disease onset, rate of progression, arrhythmias, and severity of myopathy. To begin to address whether t...

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Autores principales: Yang, Jiajia, Argenziano, Mariana A., Burgos Angulo, Mariana, Bertalovitz, Alexander, Beidokhti, Maliheh Najari, McDonald, Thomas V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716763/
https://www.ncbi.nlm.nih.gov/pubmed/34975533
http://dx.doi.org/10.3389/fphys.2021.778982
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author Yang, Jiajia
Argenziano, Mariana A.
Burgos Angulo, Mariana
Bertalovitz, Alexander
Beidokhti, Maliheh Najari
McDonald, Thomas V.
author_facet Yang, Jiajia
Argenziano, Mariana A.
Burgos Angulo, Mariana
Bertalovitz, Alexander
Beidokhti, Maliheh Najari
McDonald, Thomas V.
author_sort Yang, Jiajia
collection PubMed
description Mutations in the LMNA gene (encoding lamin A/C) are a significant cause of familial arrhythmogenic cardiomyopathy. Although the penetrance is high, there is considerable phenotypic variability in disease onset, rate of progression, arrhythmias, and severity of myopathy. To begin to address whether this variability stems from specific LMNA mutation sites and types, we generated seven patient-specific induced pluripotent stem cell (iPSC) lines with various LMNA mutations. IPSC-derived cardiomyocytes (iCMs) and cardiac fibroblasts (iCFs) were differentiated from each line for phenotypic analyses. LMNA expression and extracellular signal-regulated kinase pathway activation were perturbed to differing degrees in both iCMs and iCFs from the different lines. Enhanced apoptosis was observed in iCMs but not in iCFs. Markedly diverse irregularities of nuclear membrane morphology were present in iCFs but not iCMs, while iCMs demonstrated variable sarcomere disarray. Heterogenous electrophysiological aberrations assayed by calcium indicator imaging and multi-electrode array suggest differing substrates for arrhythmia that were accompanied by variable ion channel gene expression in the iCMs. Coculture studies suggest enhancement of the LMNA mutation effects on electrophysiological function exerted by iCFs. This study supports the utility of patient-specific iPSC experimental platform in the exploration of mechanistic and phenotypic heterogeneity of different mutations within a cardiac disease-associated gene. The addition of genetically defined coculture of cardiac-constituent non-myocytes further expands the capabilities of this approach.
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spelling pubmed-87167632021-12-31 Phenotypic Variability in iPSC-Induced Cardiomyocytes and Cardiac Fibroblasts Carrying Diverse LMNA Mutations Yang, Jiajia Argenziano, Mariana A. Burgos Angulo, Mariana Bertalovitz, Alexander Beidokhti, Maliheh Najari McDonald, Thomas V. Front Physiol Physiology Mutations in the LMNA gene (encoding lamin A/C) are a significant cause of familial arrhythmogenic cardiomyopathy. Although the penetrance is high, there is considerable phenotypic variability in disease onset, rate of progression, arrhythmias, and severity of myopathy. To begin to address whether this variability stems from specific LMNA mutation sites and types, we generated seven patient-specific induced pluripotent stem cell (iPSC) lines with various LMNA mutations. IPSC-derived cardiomyocytes (iCMs) and cardiac fibroblasts (iCFs) were differentiated from each line for phenotypic analyses. LMNA expression and extracellular signal-regulated kinase pathway activation were perturbed to differing degrees in both iCMs and iCFs from the different lines. Enhanced apoptosis was observed in iCMs but not in iCFs. Markedly diverse irregularities of nuclear membrane morphology were present in iCFs but not iCMs, while iCMs demonstrated variable sarcomere disarray. Heterogenous electrophysiological aberrations assayed by calcium indicator imaging and multi-electrode array suggest differing substrates for arrhythmia that were accompanied by variable ion channel gene expression in the iCMs. Coculture studies suggest enhancement of the LMNA mutation effects on electrophysiological function exerted by iCFs. This study supports the utility of patient-specific iPSC experimental platform in the exploration of mechanistic and phenotypic heterogeneity of different mutations within a cardiac disease-associated gene. The addition of genetically defined coculture of cardiac-constituent non-myocytes further expands the capabilities of this approach. Frontiers Media S.A. 2021-12-16 /pmc/articles/PMC8716763/ /pubmed/34975533 http://dx.doi.org/10.3389/fphys.2021.778982 Text en Copyright © 2021 Yang, Argenziano, Burgos Angulo, Bertalovitz, Najari Beidokhti and McDonald. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Yang, Jiajia
Argenziano, Mariana A.
Burgos Angulo, Mariana
Bertalovitz, Alexander
Beidokhti, Maliheh Najari
McDonald, Thomas V.
Phenotypic Variability in iPSC-Induced Cardiomyocytes and Cardiac Fibroblasts Carrying Diverse LMNA Mutations
title Phenotypic Variability in iPSC-Induced Cardiomyocytes and Cardiac Fibroblasts Carrying Diverse LMNA Mutations
title_full Phenotypic Variability in iPSC-Induced Cardiomyocytes and Cardiac Fibroblasts Carrying Diverse LMNA Mutations
title_fullStr Phenotypic Variability in iPSC-Induced Cardiomyocytes and Cardiac Fibroblasts Carrying Diverse LMNA Mutations
title_full_unstemmed Phenotypic Variability in iPSC-Induced Cardiomyocytes and Cardiac Fibroblasts Carrying Diverse LMNA Mutations
title_short Phenotypic Variability in iPSC-Induced Cardiomyocytes and Cardiac Fibroblasts Carrying Diverse LMNA Mutations
title_sort phenotypic variability in ipsc-induced cardiomyocytes and cardiac fibroblasts carrying diverse lmna mutations
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716763/
https://www.ncbi.nlm.nih.gov/pubmed/34975533
http://dx.doi.org/10.3389/fphys.2021.778982
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