Genome Editing of Isogenic Human Induced Pluripotent Stem Cells Recapitulates Long QT Phenotype for Drug Testing
Abstract Background Human induced pluripotent stem cells (iPSCs) play an important role in disease modeling and drug testing. However, the current methods are time-consuming and lack an isogenic control. Objectives This study sought to establish an efficient technology to generate human PSC-based di...
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| Veröffentlicht in: | Journal of the American College of Cardiology 2014-08, Vol.64 (5), p.451-459 |
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| creator | Wang, Yongming, PhD Liang, Ping, MD, PhD Lan, Feng, PhD Wu, Haodi, PhD Lisowski, Leszek, PhD Gu, Mingxia, MD, PhD Hu, Shijun, PhD Kay, Mark A., MD, PhD Urnov, Fyodor D., PhD Shinnawi, Rami, PhD Gold, Joseph D., PhD Gepstein, Lior, MD, PhD Wu, Joseph C., MD, PhD |
| description | Abstract Background Human induced pluripotent stem cells (iPSCs) play an important role in disease modeling and drug testing. However, the current methods are time-consuming and lack an isogenic control. Objectives This study sought to establish an efficient technology to generate human PSC-based disease models with isogenic control. Methods The ion channel genes KCNQ1 and KCNH2 with dominant negative mutations causing long QT syndrome types 1 and 2, respectively, were stably integrated into a safe harbor AAVS1 locus using zinc finger nuclease technology. Results Patch-clamp recording revealed that the edited iPSC-derived cardiomyocytes (iPSC-CMs) displayed characteristic long QT syndrome phenotype and significant prolongation of the action potential duration compared with the unedited control cells. Finally, addition of nifedipine (L-type calcium channel blocker) or pinacidil (KATP-channel opener) shortened the action potential duration of iPSC-CMs, confirming the validity of isogenic iPSC lines for drug testing in the future. Conclusions Our study demonstrates that iPSC-CM-based disease models can be rapidly generated by overexpression of dominant negative gene mutants. |
| doi_str_mv | 10.1016/j.jacc.2014.04.057 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4149735</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>1_s2_0_S0735109714027429</els_id><sourcerecordid>3389106741</sourcerecordid><originalsourceid>FETCH-LOGICAL-c581t-bd7d70336630ffd4b080b19a0796e1daa3ee739e8dfcb3b8cdd01c91d820d6083</originalsourceid><addsrcrecordid>eNpdklGL1DAUhYso7rr6B3yQgAi-zHjTpE3zIsi47g4MuLrjc0iT29mMbVOTdmH-vSkz7qoQyEO-e3LuPTfLXlNYUqDlh_1yr41Z5kD5EtIpxJPsnBZFtWCFFE-zcxCsWFCQ4ix7EeMeAMqKyufZWV5AlRdCnGfDFfa-Q3Jp3ej6HfENWUe_w94Zcj11uifr3k4GLblpp-AGP2I_ktsRO7LCto3kOxo9uHFq9YiRbHzS-LYlN3dJdjwMSBofyOcw7cgW4_zDy-xZo9uIr073Rfbjy-V2db3YfL1arz5tFqao6LiorbACGCtLBk1jeQ0V1FRqELJEarVmiIJJrGxjalZXxlqgRlJb5WBLqNhF9vGoO0x1h9Yk20G3agiu0-GgvHbq35fe3amdv1eccpnmlgTenwSC_zUl86pz0aSedY9-iioNmkLOJYeEvv0P3fsp9Km9RHEpBed8FsyPlAk-xoDNgxkKag5U7dUcqJoDVZBOIVLRm7_beCj5k2AC3p0AHY1um6B74-IjV5WUHbnTPDAN_d5hUKZ1KWXd_sQDxkfDKuYK1O28O_PqUA654LlkvwHcEcBI</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1549974445</pqid></control><display><type>article</type><title>Genome Editing of Isogenic Human Induced Pluripotent Stem Cells Recapitulates Long QT Phenotype for Drug Testing</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Wang, Yongming, PhD ; Liang, Ping, MD, PhD ; Lan, Feng, PhD ; Wu, Haodi, PhD ; Lisowski, Leszek, PhD ; Gu, Mingxia, MD, PhD ; Hu, Shijun, PhD ; Kay, Mark A., MD, PhD ; Urnov, Fyodor D., PhD ; Shinnawi, Rami, PhD ; Gold, Joseph D., PhD ; Gepstein, Lior, MD, PhD ; Wu, Joseph C., MD, PhD</creator><creatorcontrib>Wang, Yongming, PhD ; Liang, Ping, MD, PhD ; Lan, Feng, PhD ; Wu, Haodi, PhD ; Lisowski, Leszek, PhD ; Gu, Mingxia, MD, PhD ; Hu, Shijun, PhD ; Kay, Mark A., MD, PhD ; Urnov, Fyodor D., PhD ; Shinnawi, Rami, PhD ; Gold, Joseph D., PhD ; Gepstein, Lior, MD, PhD ; Wu, Joseph C., MD, PhD</creatorcontrib><description>Abstract Background Human induced pluripotent stem cells (iPSCs) play an important role in disease modeling and drug testing. However, the current methods are time-consuming and lack an isogenic control. Objectives This study sought to establish an efficient technology to generate human PSC-based disease models with isogenic control. Methods The ion channel genes KCNQ1 and KCNH2 with dominant negative mutations causing long QT syndrome types 1 and 2, respectively, were stably integrated into a safe harbor AAVS1 locus using zinc finger nuclease technology. Results Patch-clamp recording revealed that the edited iPSC-derived cardiomyocytes (iPSC-CMs) displayed characteristic long QT syndrome phenotype and significant prolongation of the action potential duration compared with the unedited control cells. Finally, addition of nifedipine (L-type calcium channel blocker) or pinacidil (KATP-channel opener) shortened the action potential duration of iPSC-CMs, confirming the validity of isogenic iPSC lines for drug testing in the future. Conclusions Our study demonstrates that iPSC-CM-based disease models can be rapidly generated by overexpression of dominant negative gene mutants.</description><identifier>ISSN: 0735-1097</identifier><identifier>EISSN: 1558-3597</identifier><identifier>DOI: 10.1016/j.jacc.2014.04.057</identifier><identifier>PMID: 25082577</identifier><identifier>CODEN: JACCDI</identifier><language>eng</language><publisher>New York, NY: Elsevier</publisher><subject>Anti-Arrhythmia Agents - therapeutic use ; Biological and medical sciences ; Cardiology ; Cardiology. Vascular system ; Cardiomyocytes ; Cardiomyopathy ; Cardiovascular ; Cell Differentiation ; Cell Transdifferentiation ; Cells, Cultured ; Cloning ; Disease ; Editing ; Epigenetics ; Genes ; Genome ; Genomes ; Genotype & phenotype ; Heart ; Humans ; Induced Pluripotent Stem Cells - metabolism ; Induced Pluripotent Stem Cells - pathology ; Internal Medicine ; Long QT syndrome ; Long QT Syndrome - drug therapy ; Long QT Syndrome - genetics ; Long QT Syndrome - pathology ; Medical sciences ; Mutation ; Patch-Clamp Techniques ; Polymerase chain reaction ; Stem cells ; Studies</subject><ispartof>Journal of the American College of Cardiology, 2014-08, Vol.64 (5), p.451-459</ispartof><rights>American College of Cardiology Foundation</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.</rights><rights>Copyright Elsevier Limited Aug 5, 2014</rights><rights>2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c581t-bd7d70336630ffd4b080b19a0796e1daa3ee739e8dfcb3b8cdd01c91d820d6083</citedby><cites>FETCH-LOGICAL-c581t-bd7d70336630ffd4b080b19a0796e1daa3ee739e8dfcb3b8cdd01c91d820d6083</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28613577$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25082577$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Yongming, PhD</creatorcontrib><creatorcontrib>Liang, Ping, MD, PhD</creatorcontrib><creatorcontrib>Lan, Feng, PhD</creatorcontrib><creatorcontrib>Wu, Haodi, PhD</creatorcontrib><creatorcontrib>Lisowski, Leszek, PhD</creatorcontrib><creatorcontrib>Gu, Mingxia, MD, PhD</creatorcontrib><creatorcontrib>Hu, Shijun, PhD</creatorcontrib><creatorcontrib>Kay, Mark A., MD, PhD</creatorcontrib><creatorcontrib>Urnov, Fyodor D., PhD</creatorcontrib><creatorcontrib>Shinnawi, Rami, PhD</creatorcontrib><creatorcontrib>Gold, Joseph D., PhD</creatorcontrib><creatorcontrib>Gepstein, Lior, MD, PhD</creatorcontrib><creatorcontrib>Wu, Joseph C., MD, PhD</creatorcontrib><title>Genome Editing of Isogenic Human Induced Pluripotent Stem Cells Recapitulates Long QT Phenotype for Drug Testing</title><title>Journal of the American College of Cardiology</title><addtitle>J Am Coll Cardiol</addtitle><description>Abstract Background Human induced pluripotent stem cells (iPSCs) play an important role in disease modeling and drug testing. However, the current methods are time-consuming and lack an isogenic control. Objectives This study sought to establish an efficient technology to generate human PSC-based disease models with isogenic control. Methods The ion channel genes KCNQ1 and KCNH2 with dominant negative mutations causing long QT syndrome types 1 and 2, respectively, were stably integrated into a safe harbor AAVS1 locus using zinc finger nuclease technology. Results Patch-clamp recording revealed that the edited iPSC-derived cardiomyocytes (iPSC-CMs) displayed characteristic long QT syndrome phenotype and significant prolongation of the action potential duration compared with the unedited control cells. Finally, addition of nifedipine (L-type calcium channel blocker) or pinacidil (KATP-channel opener) shortened the action potential duration of iPSC-CMs, confirming the validity of isogenic iPSC lines for drug testing in the future. Conclusions Our study demonstrates that iPSC-CM-based disease models can be rapidly generated by overexpression of dominant negative gene mutants.</description><subject>Anti-Arrhythmia Agents - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Cardiology</subject><subject>Cardiology. Vascular system</subject><subject>Cardiomyocytes</subject><subject>Cardiomyopathy</subject><subject>Cardiovascular</subject><subject>Cell Differentiation</subject><subject>Cell Transdifferentiation</subject><subject>Cells, Cultured</subject><subject>Cloning</subject><subject>Disease</subject><subject>Editing</subject><subject>Epigenetics</subject><subject>Genes</subject><subject>Genome</subject><subject>Genomes</subject><subject>Genotype & phenotype</subject><subject>Heart</subject><subject>Humans</subject><subject>Induced Pluripotent Stem Cells - metabolism</subject><subject>Induced Pluripotent Stem Cells - pathology</subject><subject>Internal Medicine</subject><subject>Long QT syndrome</subject><subject>Long QT Syndrome - drug therapy</subject><subject>Long QT Syndrome - genetics</subject><subject>Long QT Syndrome - pathology</subject><subject>Medical sciences</subject><subject>Mutation</subject><subject>Patch-Clamp Techniques</subject><subject>Polymerase chain reaction</subject><subject>Stem cells</subject><subject>Studies</subject><issn>0735-1097</issn><issn>1558-3597</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdklGL1DAUhYso7rr6B3yQgAi-zHjTpE3zIsi47g4MuLrjc0iT29mMbVOTdmH-vSkz7qoQyEO-e3LuPTfLXlNYUqDlh_1yr41Z5kD5EtIpxJPsnBZFtWCFFE-zcxCsWFCQ4ix7EeMeAMqKyufZWV5AlRdCnGfDFfa-Q3Jp3ej6HfENWUe_w94Zcj11uifr3k4GLblpp-AGP2I_ktsRO7LCto3kOxo9uHFq9YiRbHzS-LYlN3dJdjwMSBofyOcw7cgW4_zDy-xZo9uIr073Rfbjy-V2db3YfL1arz5tFqao6LiorbACGCtLBk1jeQ0V1FRqELJEarVmiIJJrGxjalZXxlqgRlJb5WBLqNhF9vGoO0x1h9Yk20G3agiu0-GgvHbq35fe3amdv1eccpnmlgTenwSC_zUl86pz0aSedY9-iioNmkLOJYeEvv0P3fsp9Km9RHEpBed8FsyPlAk-xoDNgxkKag5U7dUcqJoDVZBOIVLRm7_beCj5k2AC3p0AHY1um6B74-IjV5WUHbnTPDAN_d5hUKZ1KWXd_sQDxkfDKuYK1O28O_PqUA654LlkvwHcEcBI</recordid><startdate>20140805</startdate><enddate>20140805</enddate><creator>Wang, Yongming, PhD</creator><creator>Liang, Ping, MD, PhD</creator><creator>Lan, Feng, PhD</creator><creator>Wu, Haodi, PhD</creator><creator>Lisowski, Leszek, PhD</creator><creator>Gu, Mingxia, MD, PhD</creator><creator>Hu, Shijun, PhD</creator><creator>Kay, Mark A., MD, PhD</creator><creator>Urnov, Fyodor D., PhD</creator><creator>Shinnawi, Rami, PhD</creator><creator>Gold, Joseph D., PhD</creator><creator>Gepstein, Lior, MD, PhD</creator><creator>Wu, Joseph C., MD, PhD</creator><general>Elsevier</general><general>Elsevier Limited</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TK</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20140805</creationdate><title>Genome Editing of Isogenic Human Induced Pluripotent Stem Cells Recapitulates Long QT Phenotype for Drug Testing</title><author>Wang, Yongming, PhD ; Liang, Ping, MD, PhD ; Lan, Feng, PhD ; Wu, Haodi, PhD ; Lisowski, Leszek, PhD ; Gu, Mingxia, MD, PhD ; Hu, Shijun, PhD ; Kay, Mark A., MD, PhD ; Urnov, Fyodor D., PhD ; Shinnawi, Rami, PhD ; Gold, Joseph D., PhD ; Gepstein, Lior, MD, PhD ; Wu, Joseph C., MD, PhD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c581t-bd7d70336630ffd4b080b19a0796e1daa3ee739e8dfcb3b8cdd01c91d820d6083</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Anti-Arrhythmia Agents - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Cardiology</topic><topic>Cardiology. Vascular system</topic><topic>Cardiomyocytes</topic><topic>Cardiomyopathy</topic><topic>Cardiovascular</topic><topic>Cell Differentiation</topic><topic>Cell Transdifferentiation</topic><topic>Cells, Cultured</topic><topic>Cloning</topic><topic>Disease</topic><topic>Editing</topic><topic>Epigenetics</topic><topic>Genes</topic><topic>Genome</topic><topic>Genomes</topic><topic>Genotype & phenotype</topic><topic>Heart</topic><topic>Humans</topic><topic>Induced Pluripotent Stem Cells - metabolism</topic><topic>Induced Pluripotent Stem Cells - pathology</topic><topic>Internal Medicine</topic><topic>Long QT syndrome</topic><topic>Long QT Syndrome - drug therapy</topic><topic>Long QT Syndrome - genetics</topic><topic>Long QT Syndrome - pathology</topic><topic>Medical sciences</topic><topic>Mutation</topic><topic>Patch-Clamp Techniques</topic><topic>Polymerase chain reaction</topic><topic>Stem cells</topic><topic>Studies</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Yongming, PhD</creatorcontrib><creatorcontrib>Liang, Ping, MD, PhD</creatorcontrib><creatorcontrib>Lan, Feng, PhD</creatorcontrib><creatorcontrib>Wu, Haodi, PhD</creatorcontrib><creatorcontrib>Lisowski, Leszek, PhD</creatorcontrib><creatorcontrib>Gu, Mingxia, MD, PhD</creatorcontrib><creatorcontrib>Hu, Shijun, PhD</creatorcontrib><creatorcontrib>Kay, Mark A., MD, PhD</creatorcontrib><creatorcontrib>Urnov, Fyodor D., PhD</creatorcontrib><creatorcontrib>Shinnawi, Rami, PhD</creatorcontrib><creatorcontrib>Gold, Joseph D., PhD</creatorcontrib><creatorcontrib>Gepstein, Lior, MD, PhD</creatorcontrib><creatorcontrib>Wu, Joseph C., MD, PhD</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of the American College of Cardiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Yongming, PhD</au><au>Liang, Ping, MD, PhD</au><au>Lan, Feng, PhD</au><au>Wu, Haodi, PhD</au><au>Lisowski, Leszek, PhD</au><au>Gu, Mingxia, MD, PhD</au><au>Hu, Shijun, PhD</au><au>Kay, Mark A., MD, PhD</au><au>Urnov, Fyodor D., PhD</au><au>Shinnawi, Rami, PhD</au><au>Gold, Joseph D., PhD</au><au>Gepstein, Lior, MD, PhD</au><au>Wu, Joseph C., MD, PhD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome Editing of Isogenic Human Induced Pluripotent Stem Cells Recapitulates Long QT Phenotype for Drug Testing</atitle><jtitle>Journal of the American College of Cardiology</jtitle><addtitle>J Am Coll Cardiol</addtitle><date>2014-08-05</date><risdate>2014</risdate><volume>64</volume><issue>5</issue><spage>451</spage><epage>459</epage><pages>451-459</pages><issn>0735-1097</issn><eissn>1558-3597</eissn><coden>JACCDI</coden><abstract>Abstract Background Human induced pluripotent stem cells (iPSCs) play an important role in disease modeling and drug testing. However, the current methods are time-consuming and lack an isogenic control. Objectives This study sought to establish an efficient technology to generate human PSC-based disease models with isogenic control. Methods The ion channel genes KCNQ1 and KCNH2 with dominant negative mutations causing long QT syndrome types 1 and 2, respectively, were stably integrated into a safe harbor AAVS1 locus using zinc finger nuclease technology. Results Patch-clamp recording revealed that the edited iPSC-derived cardiomyocytes (iPSC-CMs) displayed characteristic long QT syndrome phenotype and significant prolongation of the action potential duration compared with the unedited control cells. Finally, addition of nifedipine (L-type calcium channel blocker) or pinacidil (KATP-channel opener) shortened the action potential duration of iPSC-CMs, confirming the validity of isogenic iPSC lines for drug testing in the future. Conclusions Our study demonstrates that iPSC-CM-based disease models can be rapidly generated by overexpression of dominant negative gene mutants.</abstract><cop>New York, NY</cop><pub>Elsevier</pub><pmid>25082577</pmid><doi>10.1016/j.jacc.2014.04.057</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Anti-Arrhythmia Agents - therapeutic use Biological and medical sciences Cardiology Cardiology. Vascular system Cardiomyocytes Cardiomyopathy Cardiovascular Cell Differentiation Cell Transdifferentiation Cells, Cultured Cloning Disease Editing Epigenetics Genes Genome Genomes Genotype & phenotype Heart Humans Induced Pluripotent Stem Cells - metabolism Induced Pluripotent Stem Cells - pathology Internal Medicine Long QT syndrome Long QT Syndrome - drug therapy Long QT Syndrome - genetics Long QT Syndrome - pathology Medical sciences Mutation Patch-Clamp Techniques Polymerase chain reaction Stem cells Studies |
| title | Genome Editing of Isogenic Human Induced Pluripotent Stem Cells Recapitulates Long QT Phenotype for Drug Testing |
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