Plakophilin-2 truncating variants impair cardiac contractility by disrupting sarcomere stability and organization

doi:10.1126/sciadv.abh3995

IMECH-IR > 非线性力学国家重点实验室

	Plakophilin-2 truncating variants impair cardiac contractility by disrupting sarcomere stability and organization
	Zhang, KH 1,2; Cloonan, PE.1; Sundaram, S 1,2; Liu F(刘峰)3; Das, SL 1,2,4; Ewoldt, JK 1,2; Bays, JL 1,2; Tomp, S 1; Toepfer, CN 5,6; Marsiglia, JDC 5; Gorham, J 5; Reichart, D 5; Eyckmans, J 1,2; Seidman, JG 5; Seidman, CE 5,7,8; Chen, CS 1,2
通讯作者	Chen, Christopher S.(chencs@bu.edu)
发表期刊	SCIENCE ADVANCES
	2021-10-01
卷号	7 期号:42 页码:14
ISSN	2375-2548
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.
DOI	10.1126/sciadv.abh3995
收录类别	SCI ; EI
语种	英语
WOS记录号	WOS:000707571700018
关键词[WOS]	PLURIPOTENT STEM-CELLS ; HEART-MUSCLE CELLS ; ALPHA-T-CATENIN ; ARRHYTHMOGENIC CARDIOMYOPATHY ; ADHERING JUNCTIONS ; AREA-COMPOSITA ; PATIENT ; CARDIOMYOCYTES ; MECHANISMS ; LEADS
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
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]
项目资助者	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
论文分区	一类
力学所作者排名	3+
RpAuthor	Chen, Christopher S.
引用统计	被引频次：11[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://dspace.imech.ac.cn/handle/311007/87618
专题	非线性力学国家重点实验室
作者单位	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
推荐引用方式 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.
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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