Abnormal Calcium Handling Properties Underlie Familial Hypertrophic Cardiomyopathy Pathology in Patient-Specific Induced Pluripotent Stem Cells

被引：511

作者：

Lan, Feng ^{[1
,2
,3
]}

Lee, Andrew S. ^{[1
,2
,3
]}

Liang, Ping ^{[1
,2
,3
]}

Sanchez-Freire, Veronica ^{[1
,2
,3
]}

Nguyen, Patricia K. ^{[1
,2
]}

Wang, Li ^{[1
,2
]}

Han, Leng ^{[1
,2
]}

Yen, Michelle ^{[4
]}

Wang, Yongming ^{[1
,2
,3
]}

Sun, Ning ^{[1
,2
]}

Abilez, Oscar J. ^{[5
]}

Hu, Shijun ^{[1
,2
,3
]}

Ebert, Antje D. ^{[1
,2
,3
]}

Navarrete, Enrique G. ^{[2
]}

Simmons, Chelsey S. ^{[9
]}

Wheeler, Matthew ^{[1
]}

Pruitt, Beth ^{[9
]}

Lewis, Richard ^{[4
]}

Yamaguchi, Yoshinori ^{[10
]}

Ashley, Euan A. ^{[1
]}

Bers, Donald M. ^{[11
]}

Robbins, Robert C. ^{[2
,6
]}

Longaker, Michael T. ^{[3
,8
]}

Wu, Joseph C. ^{[1
,2
,3
,7
]}

机构：

[1] Stanford Univ, Dept Med, Div Cardiol, Sch Med, Stanford, CA 94305 USA

[2] Stanford Univ, Stanford Cardiovasc Inst, Sch Med, Stanford, CA 94305 USA

[3] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Sch Med, Stanford, CA 94305 USA

[4] Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA

[5] Stanford Univ, Dept Surg, Div Vasc Surg, Sch Med, Stanford, CA 94305 USA

[6] Stanford Univ, Dept Cardiothorac Surg, Sch Med, Stanford, CA 94305 USA

[7] Stanford Univ, Dept Radiol, Mol Imaging Program, Sch Med, Stanford, CA 94305 USA

[8] Stanford Univ, Dept Surg, Div Plast & Reconstruct Surg, Sch Med, Stanford, CA 94305 USA

[9] Stanford Univ, Dept Mech Engn, Sch Engn, Stanford, CA 94305 USA

[10] Osaka Univ, Dept Appl Phys, Suita, Osaka 5650871, Japan

[11] Univ Calif Davis, Dept Pharmacol, Davis, CA 95616 USA

来源：

CELL STEM CELL | 2013年 / 12卷 / 01期

关键词：

TROPONIN-T; MYOSIN; MECHANISMS; MUTATION; MODELS;

D O I：

10.1016/j.stem.2012.10.010

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Familial hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiac disorder linked to arrhythmia and sudden cardiac death. While the causes of HCM have been identified as genetic mutations in the cardiac sarcomere, the pathways by which sarcomeric mutations engender myocyte hypertrophy and electrophysiological abnormalities are not understood. To elucidate the mechanisms underlying HCM development, we generated patient-specific induced pluripotent stem cell cardiornyocytes (iPSC-CMs) from a ten-member family cohort carrying a hereditary HCM missense mutation (Arg663His) in the MYH7 gene. Diseased iPSC-CMs recapitulated numerous aspects of the HCM phenotype including cellular enlargement and contractile arrhythmia at the single-cell level. Calcium (Ca2+) imaging indicated dysregulation of Ca2+ cycling and elevation in intracellular Ca2+ ([Ca2+](i)) are central mechanisms for disease pathogenesis. Pharmacological restoration of Ca2+ homeostasis prevented development of hypertrophy and electrophysiological irregularities. We anticipate that these findings will help elucidate the mechanisms underlying HCM development and identify novel therapies for the disease.

引用

页码：101 / 113

页数：13

共 36 条

[11] A MOLECULAR-BASIS FOR FAMILIAL HYPERTROPHIC CARDIOMYOPATHY - A BETA-CARDIAC MYOSIN HEAVY-CHAIN GENE MISSENSE MUTATION [J].