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Modeling human protein aggregation cardiomyopathy using murine induced pluripotent stem cells. Stem Cells Transl Med 2013 Mar;2(3):161-6



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Several mutations in αB-crystallin (CryAB), a heat shock protein with chaperone-like activities, are causally linked to skeletal and cardiac myopathies in humans. To better understand the underlying pathogenic mechanisms, we had previously generated transgenic (TG) mice expressing R120GCryAB, which recapitulated distinguishing features of the myopathic disorder (e.g., protein aggregates, hypertrophic cardiomyopathy). To determine whether induced pluripotent stem cell (iPSC)-derived cardiomyocytes, a new experimental approach for human disease modeling, would be relevant to aggregation-prone disorders, we decided to exploit the existing transgenic mouse model to derive iPSCs from tail tip fibroblasts. Several iPSC lines were generated from TG and non-TG mice and validated for pluripotency. TG iPSC-derived cardiomyocytes contained perinuclear aggregates positive for CryAB staining, whereas CryAB protein accumulated in both detergent-soluble and insoluble fractions. iPSC-derived cardiomyocytes identified by cardiac troponin T staining were significantly larger when expressing R120GCryAB at a high level in comparison with TG low expressor or non-TG cells. Expression of fetal genes such as atrial natriuretic factor, B-type natriuretic peptide, and α-skeletal α-actin, assessed by quantitative reverse transcription-polymerase chain reaction, were increased in TG cardiomyocytes compared with non-TG, indicating the activation of the hypertrophic genetic program in vitro. Our study demonstrates for the first time that differentiation of R120G iPSCs into cardiomyocytes causes protein aggregation and cellular hypertrophy, recapitulating in vitro key pathognomonic hallmarks found in both animal models and patients. Our findings pave the way for further studies exploiting this cell model system for mechanistic and therapeutic investigations.

Author List

Limphong P, Zhang H, Christians E, Liu Q, Riedel M, Ivey K, Cheng P, Mitzelfelt K, Taylor G, Winge D, Srivastava D, Benjamin I


Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Atrial Natriuretic Factor
Cardiomyopathy, Hypertrophic
Cell Differentiation
Cell Line
Gene Expression Regulation
Induced Pluripotent Stem Cells
Mice, Transgenic
Myocytes, Cardiac
Natriuretic Peptide, Brain
Protein Multimerization
Reverse Transcriptase Polymerase Chain Reaction
Troponin T
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a