| Plakophilin-2 truncating variants impair cardiac contractility by disrupting sarcomere stability and organization | |
| Zhang, KH1,2; Cloonan, PE.1; Sundaram, S1,2; Liu F(刘峰)3; Das, SL1,2,4; Ewoldt, JK1,2; Bays, JL1,2; Tomp, S1; Toepfer, CN5,6; Marsiglia, JDC5; Gorham, J5; Reichart, D5; Eyckmans, J1,2; Seidman, JG5; Seidman, CE5,7,8; Chen, CS1,2 | |
| Corresponding Author | Chen, Christopher S.([email protected]) |
| Source Publication | SCIENCE ADVANCES
 |
| 2021-10-01 | |
| Volume | 7Issue:42Pages:14 |
| ISSN | 2375-2548 |
| Abstract | 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. |
| DOI | 10.1126/sciadv.abh3995 |
| Indexed By | SCI ; EI |
| Language | 英语 |
| WOS ID | WOS:000707571700018 |
| WOS Keyword | PLURIPOTENT STEM-CELLS ; HEART-MUSCLE CELLS ; ALPHA-T-CATENIN ; ARRHYTHMOGENIC CARDIOMYOPATHY ; ADHERING JUNCTIONS ; AREA-COMPOSITA ; PATIENT ; CARDIOMYOCYTES ; MECHANISMS ; LEADS |
| WOS Research Area | Science & Technology - Other Topics |
| WOS Subject | Multidisciplinary Sciences |
| Funding Project | 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] |
| Funding Organization | 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 |
| Classification | 一类 |
| Ranking | 3+ |
| Contributor | Chen, Christopher S. |
| Citation statistics | |
| Document Type | 期刊论文 |
| Identifier | http://dspace.imech.ac.cn/handle/311007/87618 |
| Collection | 非线性力学国家重点实验室 |
| Affiliation | 1.Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA; 2.Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA; 3.Chinese Acad Sci, Inst Mech, State Key Lab Nonlinear Mech, Beijing 100190, Peoples R China; 4.MIT, Harvard MIT Program Hlth Sci & Technol, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA; 5.Harvard Med Sch, Dept Genet, Boston, MA 02115 USA; 6.Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford OX3 9DU, England; 7.Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA; 8.Howard Hughes Med Inst, Chevy Chase, MD 20815 USA |
| Recommended Citation GB/T 7714 | Zhang, KH,Cloonan, PE.,Sundaram, S,et al. Plakophilin-2 truncating variants impair cardiac contractility by disrupting sarcomere stability and organization[J]. SCIENCE ADVANCES,2021,7,42,:14.Rp_Au:Chen, Christopher S. |
| APA | Zhang, KH.,Cloonan, PE..,Sundaram, S.,刘峰.,Das, SL.,...&Chen, CS.(2021).Plakophilin-2 truncating variants impair cardiac contractility by disrupting sarcomere stability and organization.SCIENCE ADVANCES,7(42),14. |
| MLA | Zhang, KH,et al."Plakophilin-2 truncating variants impair cardiac contractility by disrupting sarcomere stability and organization".SCIENCE ADVANCES 7.42(2021):14. |
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| Jp2021F537.pdf（1131KB） | 期刊论文 | 出版稿 | 开放获取 | CC BY-NC-SA | View Download | |
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