Plakophilin-2 truncating variants impair cardiac contractility by disrupting sarcomere stability and organization
文献类型：期刊论文
| 作者 | Zhang, Kehan7,8; Cloonan, Paige E.8; Sundaram, Subramanian7,8; Liu, Feng6; Das, Shoshana L.5,7,8; Ewoldt, Jourdan K.7,8; Bays, Jennifer L.7,8; Tomp, Samuel8; Toepfer, Christopher N.3,4; Marsiglia, Julia D. C.4 |
| 刊名 | SCIENCE ADVANCES
 |
| 出版日期 | 2021-10-01 |
| 卷号 | 7期号:42页码:14 |
| ISSN号 | 2375-2548 |
| DOI | 10.1126/sciadv.abh3995 |
| 通讯作者 | Chen, Christopher S.(chencs@bu.edu) |
| 英文摘要 | Progressive loss of cardiac systolic function in arrhythmogenic cardiomyopathy (ACM) has recently gained attention as an important clinical consideration in managing the disease. However, the mechanisms leading to reduction in cardiac contractility are poorly defined. Here, we use CRISPR gene editing to generate human induced pluripotent stem cells (iPSCs) that harbor plakophilin-2 truncating variants (PKP2tv), the most prevalent ACM-linked mutations. The PKP2tv iPSC-derived cardiomyocytes are shown to have aberrant action potentials and reduced systolic function in cardiac microtissues, recapitulating both the electrical and mechanical pathologies reported in ACM. By combining cell micropatterning with traction force microscopy and live imaging, we found that PKP2tvs impair cardiac tissue contractility by destabilizing cell-cell junctions and in turn disrupting sarcomere stability and organization. These findings highlight the interplay between cell-cell adhesions and sarcomeres required for stabilizing cardiomyocyte structure and function and suggest fundamental pathogenic mechanisms that may be shared among different types of cardiomyopathies. |
| WOS关键词 | PLURIPOTENT STEM-CELLS ; HEART-MUSCLE CELLS ; ALPHA-T-CATENIN ; ARRHYTHMOGENIC CARDIOMYOPATHY ; ADHERING JUNCTIONS ; AREA-COMPOSITA ; PATIENT ; CARDIOMYOCYTES ; MECHANISMS ; LEADS |
| 资助项目 | National Science Foundation Engineering Research Center on Cellular Metamaterials grant[EEC-1647837] ; National Science Foundation Science and Technology Center for Engineering Mechanobiology grant[CMMI-1548571] ; National Institute of Health National Heart Lung and Blood Institute[HL080494] ; American Heart Association[17PRE33660967] ; American Heart Association[20POST35210045] ; China Scholarship Council scholarship[201804910161] ; National Science Foundation[DGE-1122374] ; National Science Foundation[DGE-1840990] ; Boston University Presidential Scholarship ; Sir Henry Wellcome Fellowship[206466/Z/17/Z] ; Leducq Foundation ; Howard Hughes Medical Institute ; BHF CRE Intermediate Transition Fellowship[RE/18/3/34214] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000707571700018 |
| 资助机构 | National Science Foundation Engineering Research Center on Cellular Metamaterials grant ; National Science Foundation Science and Technology Center for Engineering Mechanobiology grant ; National Institute of Health National Heart Lung and Blood Institute ; American Heart Association ; China Scholarship Council scholarship ; National Science Foundation ; Boston University Presidential Scholarship ; Sir Henry Wellcome Fellowship ; Leducq Foundation ; Howard Hughes Medical Institute ; BHF CRE Intermediate Transition Fellowship |
| 源URL | [http://dspace.imech.ac.cn/handle/311007/87617]  |
| 专题 | 力学研究所_非线性力学国家重点实验室 |
| 通讯作者 | Chen, Christopher S. |
| 作者单位 | 1.Howard Hughes Med Inst, Chevy Chase, MD 20815 USA 2.Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA 3.Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford OX3 9DU, England 4.Harvard Med Sch, Dept Genet, Boston, MA 02115 USA 5.MIT, Harvard MIT Program Hlth Sci & Technol, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA 6.Chinese Acad Sci, Inst Mech, State Key Lab Nonlinear Mech, Beijing 100190, Peoples R China 7.Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA 8.Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA |
| 推荐引用方式 GB/T 7714 | Zhang, Kehan,Cloonan, Paige E.,Sundaram, Subramanian,et al. Plakophilin-2 truncating variants impair cardiac contractility by disrupting sarcomere stability and organization[J]. SCIENCE ADVANCES,2021,7(42):14. |
| APA | Zhang, Kehan.,Cloonan, Paige E..,Sundaram, Subramanian.,Liu, Feng.,Das, Shoshana L..,...&刘峰.(2021).Plakophilin-2 truncating variants impair cardiac contractility by disrupting sarcomere stability and organization.SCIENCE ADVANCES,7(42),14. |
| MLA | Zhang, Kehan,et al."Plakophilin-2 truncating variants impair cardiac contractility by disrupting sarcomere stability and organization".SCIENCE ADVANCES 7.42(2021):14. |
入库方式： OAI收割
来源：力学研究所
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