PMID- 33962658
OWN - NLM
STAT- MEDLINE
DCOM- 20210712
LR  - 20210712
IS  - 1757-6512 (Electronic)
IS  - 1757-6512 (Linking)
VI  - 12
IP  - 1
DP  - 2021 May 7
TI  - hERG-deficient human embryonic stem cell-derived cardiomyocytes for modelling QT 
      prolongation.
PG  - 278
LID - 10.1186/s13287-021-02346-1 [doi]
LID - 278
AB  - BACKGROUND: Long-QT syndrome type 2 (LQT2) is a common malignant hereditary 
      arrhythmia. Due to the lack of suitable animal and human models, the pathogenesis 
      of LQT2 caused by human ether-a-go-go-related gene (hERG) deficiency is still 
      unclear. In this study, we generated an hERG-deficient human cardiomyocyte (CM) 
      model that simulates 'human homozygous hERG mutations' to explore the underlying 
      impact of hERG dysfunction and the genotype-phenotype relationship of hERG 
      deficiency. METHODS: The KCNH2 was knocked out in the human embryonic stem cell 
      (hESC) H9 line using the CRISPR/Cas9 system. Using a chemically defined 
      differentiation protocol, we obtained and verified hERG-deficient CMs. 
      Subsequently, high-throughput microelectrode array (MEA) assays and drug 
      interventions were performed to characterise the electrophysiological signatures 
      of hERG-deficient cell lines. RESULTS: Our results showed that KCNH2 knockout did 
      not affect the pluripotency or differentiation efficiency of H9 cells. Using 
      high-throughput MEA assays, we found that the electric field potential duration 
      and action potential duration of hERG-deficient CMs were significantly longer 
      than those of normal CMs. The hERG-deficient lines also exhibited irregular 
      rhythm and some early afterdepolarisations. Moreover, we used the hERG-deficient 
      human CM model to evaluate the potency of agents (nifedipine and magnesium 
      chloride) that may ameliorate the phenotype. CONCLUSIONS: We established an 
      hERG-deficient human CM model that exhibited QT prolongation, irregular rhythm 
      and sensitivity to other ion channel blockers. This model serves as an important 
      tool that can aid in understanding the fundamental impact of hERG dysfunction, 
      elucidate the genotype-phenotype relationship of hERG deficiency and facilitate 
      drug development.
FAU - Chang, Yun
AU  - Chang Y
AD  - Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of 
      Biomedical Engineering for Cardiovascular Disease Research, The Key Laboratory of 
      Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen 
      Hospital, Capital Medical University, Research Institute Building, Room 323, 2 
      Anzhen Road, Chaoyang District, Beijing, 100029, China.
AD  - Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, 
      China.
FAU - Li, Ya-Nan
AU  - Li YN
AD  - Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of 
      Biomedical Engineering for Cardiovascular Disease Research, The Key Laboratory of 
      Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen 
      Hospital, Capital Medical University, Research Institute Building, Room 323, 2 
      Anzhen Road, Chaoyang District, Beijing, 100029, China.
AD  - Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, 
      China.
FAU - Bai, Rui
AU  - Bai R
AD  - Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of 
      Biomedical Engineering for Cardiovascular Disease Research, The Key Laboratory of 
      Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen 
      Hospital, Capital Medical University, Research Institute Building, Room 323, 2 
      Anzhen Road, Chaoyang District, Beijing, 100029, China.
AD  - Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, 
      China.
FAU - Wu, Fujian
AU  - Wu F
AD  - Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of 
      Biomedical Engineering for Cardiovascular Disease Research, The Key Laboratory of 
      Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen 
      Hospital, Capital Medical University, Research Institute Building, Room 323, 2 
      Anzhen Road, Chaoyang District, Beijing, 100029, China.
AD  - Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, 
      China.
FAU - Ma, Shuhong
AU  - Ma S
AD  - Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of 
      Biomedical Engineering for Cardiovascular Disease Research, The Key Laboratory of 
      Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen 
      Hospital, Capital Medical University, Research Institute Building, Room 323, 2 
      Anzhen Road, Chaoyang District, Beijing, 100029, China.
AD  - Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, 
      China.
FAU - Saleem, Amina
AU  - Saleem A
AD  - Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of 
      Biomedical Engineering for Cardiovascular Disease Research, The Key Laboratory of 
      Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen 
      Hospital, Capital Medical University, Research Institute Building, Room 323, 2 
      Anzhen Road, Chaoyang District, Beijing, 100029, China.
AD  - Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, 
      China.
FAU - Zhang, Siyao
AU  - Zhang S
AD  - Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of 
      Biomedical Engineering for Cardiovascular Disease Research, The Key Laboratory of 
      Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen 
      Hospital, Capital Medical University, Research Institute Building, Room 323, 2 
      Anzhen Road, Chaoyang District, Beijing, 100029, China.
AD  - Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, 
      China.
FAU - Jiang, Youxu
AU  - Jiang Y
AD  - Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of 
      Biomedical Engineering for Cardiovascular Disease Research, The Key Laboratory of 
      Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen 
      Hospital, Capital Medical University, Research Institute Building, Room 323, 2 
      Anzhen Road, Chaoyang District, Beijing, 100029, China.
AD  - Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, 
      China.
FAU - Dong, Tao
AU  - Dong T
AD  - Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of 
      Biomedical Engineering for Cardiovascular Disease Research, The Key Laboratory of 
      Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen 
      Hospital, Capital Medical University, Research Institute Building, Room 323, 2 
      Anzhen Road, Chaoyang District, Beijing, 100029, China.
AD  - Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, 
      China.
FAU - Guo, Tianwei
AU  - Guo T
AD  - Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of 
      Biomedical Engineering for Cardiovascular Disease Research, The Key Laboratory of 
      Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen 
      Hospital, Capital Medical University, Research Institute Building, Room 323, 2 
      Anzhen Road, Chaoyang District, Beijing, 100029, China.
AD  - Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, 
      China.
FAU - Hang, Chengwen
AU  - Hang C
AD  - Department of Cardiology, Peking University Third Hospital, Beijing, 100191, 
      China.
FAU - Lu, Wen-Jing
AU  - Lu WJ
AD  - Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of 
      Biomedical Engineering for Cardiovascular Disease Research, The Key Laboratory of 
      Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen 
      Hospital, Capital Medical University, Research Institute Building, Room 323, 2 
      Anzhen Road, Chaoyang District, Beijing, 100029, China.
AD  - Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, 
      China.
FAU - Jiang, Hongfeng
AU  - Jiang H
AD  - Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of 
      Biomedical Engineering for Cardiovascular Disease Research, The Key Laboratory of 
      Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen 
      Hospital, Capital Medical University, Research Institute Building, Room 323, 2 
      Anzhen Road, Chaoyang District, Beijing, 100029, China. hfjiang@ccmu.edu.cn.
AD  - Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, 
      China. hfjiang@ccmu.edu.cn.
FAU - Lan, Feng
AU  - Lan F
AUID- ORCID: 0000-0002-9038-4014
AD  - Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of 
      Biomedical Engineering for Cardiovascular Disease Research, The Key Laboratory of 
      Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen 
      Hospital, Capital Medical University, Research Institute Building, Room 323, 2 
      Anzhen Road, Chaoyang District, Beijing, 100029, China. fenglan@ccmu.edu.cn.
AD  - Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, 
      China. fenglan@ccmu.edu.cn.
AD  - State Key Laboratory of Cardiovascular Disease, National Center for 
      Cardiovascular Diseases, Fuwai Hospital, Key Laboratory of Application of 
      Pluripotent Stem Cells in Heart Regeneration, Chinese Academy of Medical Sciences 
      and Peking Union Medical College, Beijing, China. fenglan@ccmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210507
PL  - England
TA  - Stem Cell Res Ther
JT  - Stem cell research & therapy
JID - 101527581
RN  - 0 (ERG1 Potassium Channel)
RN  - 0 (Ether-A-Go-Go Potassium Channels)
SB  - IM
MH  - Animals
MH  - ERG1 Potassium Channel/genetics
MH  - Ether-A-Go-Go Potassium Channels/genetics
MH  - *Human Embryonic Stem Cells
MH  - Humans
MH  - *Long QT Syndrome/genetics
MH  - Myocytes, Cardiac
PMC - PMC8103639
OTO - NOTNLM
OT  - CRISPR/Cas9
OT  - Human ether-a-go-go-related gene
OT  - KCNH2
OT  - QT prolongation
OT  - hESCs
COIS- The authors declare that they have no competing interests.
EDAT- 2021/05/09 06:00
MHDA- 2021/07/13 06:00
PMCR- 2021/05/07
CRDT- 2021/05/08 06:10
PHST- 2021/02/11 00:00 [received]
PHST- 2021/04/19 00:00 [accepted]
PHST- 2021/05/08 06:10 [entrez]
PHST- 2021/05/09 06:00 [pubmed]
PHST- 2021/07/13 06:00 [medline]
PHST- 2021/05/07 00:00 [pmc-release]
AID - 10.1186/s13287-021-02346-1 [pii]
AID - 2346 [pii]
AID - 10.1186/s13287-021-02346-1 [doi]
PST - epublish
SO  - Stem Cell Res Ther. 2021 May 7;12(1):278. doi: 10.1186/s13287-021-02346-1.