Study familial hypertrophic cardiomyopathy using patient-specific induced pluripotent stem cells

Lu Han; Yang Li; Jason Tchao; Aaron D Kaplan; Bo Lin; You Li; Jocelyn Mich-Basso; Agnieszka Lis; Narmeen Hassan; Barry London; Glenna C L Bett; Kimimasa Tobita; Randall L Rasmusson; Lei Yang

doi:10.1093/cvr/cvu205

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Study familial hypertrophic cardiomyopathy using patient-specific induced pluripotent stem cells

Journal article

Open access

Peer reviewed

Study familial hypertrophic cardiomyopathy using patient-specific induced pluripotent stem cells

Lu Han, Yang Li, Jason Tchao, Aaron D Kaplan, Bo Lin, You Li, Jocelyn Mich-Basso, Agnieszka Lis, Narmeen Hassan, Barry London, …

Cardiovascular research, Vol.104(2), pp.258-269

11/01/2014

DOI: 10.1093/cvr/cvu205

PMCID: PMC4217687

PMID: 25209314

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Abstract

Familial hypertrophic cardiomyopathy (HCM) is one the most common heart disorders, with gene mutations in the cardiac sarcomere. Studying HCM with patient-specific induced pluripotent stem-cell (iPSC)-derived cardiomyocytes (CMs) would benefit the understanding of HCM mechanism, as well as the development of personalized therapeutic strategies. To investigate the molecular mechanism underlying the abnormal CM functions in HCM, we derived iPSCs from an HCM patient with a single missense mutation (Arginine442Glycine) in the MYH7 gene. CMs were next enriched from HCM and healthy iPSCs, followed with whole transcriptome sequencing and pathway enrichment analysis. A widespread increase of genes responsible for 'Cell Proliferation' was observed in HCM iPSC-CMs when compared with control iPSC-CMs. Additionally, HCM iPSC-CMs exhibited disorganized sarcomeres and electrophysiological irregularities. Furthermore, disease phenotypes of HCM iPSC-CMs were attenuated with pharmaceutical treatments. Overall, this study explored the possible patient-specific and mutation-specific disease mechanism of HCM, and demonstrates the potential of using HCM iPSC-CMs for future development of therapeutic strategies. Additionally, the whole methodology established in this study could be utilized to study mechanisms of other human-inherited heart diseases.

Phenotype

Cardiomyopathy, Hypertrophic, Familial - genetics

Humans

Transcriptome

Myosin Heavy Chains - genetics

Gene Regulatory Networks

Case-Control Studies

Cellular Reprogramming

Action Potentials

Cellular Reprogramming Techniques

Adult

Female

Induced Pluripotent Stem Cells - metabolism

Cell Proliferation - genetics

Genetic Predisposition to Disease

Induced Pluripotent Stem Cells - drug effects

Sarcomeres - metabolism

Cardiac Myosins - genetics

Cardiomyopathy, Hypertrophic, Familial - pathology

Cells, Cultured

Gene Expression Regulation

Cardiomyopathy, Hypertrophic, Familial - metabolism

Gene Expression Profiling - methods

Induced Pluripotent Stem Cells - ultrastructure

Cell Separation - methods

Mice, SCID

Sarcomeres - ultrastructure

Animals

Myocytes, Cardiac - drug effects

Myocytes, Cardiac - metabolism

Mice, Inbred NOD

Calcium Signaling - genetics

Myocytes, Cardiac - ultrastructure

Details

Title: Subtitle: Study familial hypertrophic cardiomyopathy using patient-specific induced pluripotent stem cells
Creators: Lu Han - Department of Developmental Biology, University of Pittsburgh School of Medicine, 8117 Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA
Yang Li - Department of Developmental Biology, University of Pittsburgh School of Medicine, 8117 Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA
Jason Tchao - Department of Developmental Biology, University of Pittsburgh School of Medicine, 8117 Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA
Aaron D Kaplan - Center for Cellular and Systems Electrophysiology, Department of Physiology and Biophysics, SUNY, Buffalo, NY 14214, USA
Bo Lin - Department of Developmental Biology, University of Pittsburgh School of Medicine, 8117 Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA
You Li - University of Pittsburgh
Jocelyn Mich-Basso - Department of Developmental Biology, University of Pittsburgh School of Medicine, 8117 Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA
Agnieszka Lis - Center for Cellular and Systems Electrophysiology, Department of Physiology and Biophysics, SUNY, Buffalo, NY 14214, USA
Narmeen Hassan - Department of Developmental Biology, University of Pittsburgh School of Medicine, 8117 Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA
Barry London - University of Iowa, Internal Medicine
Glenna C L Bett - Department of Obstetrics and Gynecology, SUNY, Buffalo, NY 14214, USA
Kimimasa Tobita - Department of Developmental Biology, University of Pittsburgh School of Medicine, 8117 Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA
Randall L Rasmusson - Center for Cellular and Systems Electrophysiology, Department of Physiology and Biophysics, SUNY, Buffalo, NY 14214, USA
Lei Yang - Department of Developmental Biology, University of Pittsburgh School of Medicine, 8117 Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA lyang@pitt.edu
Resource Type: Journal article
Publication Details: Cardiovascular research, Vol.104(2), pp.258-269
Publisher: England
DOI: 10.1093/cvr/cvu205
PMID: 25209314
PMCID: PMC4217687
ISSN: 0008-6363
eISSN: 1755-3245
Grant note: HL062465 / NHLBI NIH HHS R21 HL094402 / NHLBI NIH HHS UL1TR000005 / NCATS NIH HHS T32-HL76124 / NHLBI NIH HHS HL093631 / NHLBI NIH HHS R21 HL093631 / NHLBI NIH HHS
Language: English
Date published: 11/01/2014
Academic Unit: Molecular Physiology and Biophysics; Internal Medicine
Record Identifier: 9984048600202771

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Study familial hypertrophic cardiomyopathy using patient-specific induced pluripotent stem cells

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