{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T16:20:58Z","timestamp":1776270058306,"version":"3.50.1"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2015,3,13]],"date-time":"2015-03-13T00:00:00Z","timestamp":1426204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["U01HL098163"],"award-info":[{"award-number":["U01HL098163"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01HD057036"],"award-info":[{"award-number":["R01HD057036"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH Pathway to Independent Award","award":["R00HL11345"],"award-info":[{"award-number":["R00HL11345"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title\/>\n                  <jats:p>Reprogramming of human somatic cells to pluripotency has been used to investigate disease mechanisms and to identify potential therapeutics. However, the methods used for reprogramming, in vitro differentiation, and phenotyping are still complicated, expensive, and time-consuming. To address the limitations, we first optimized a protocol for reprogramming of human fibroblasts and keratinocytes into pluripotency using single lipofection and the episomal vectors in a 24-well plate format. This method allowed us to generate multiple lines of integration-free and feeder-free induced pluripotent stem cells (iPSCs) from seven patients with cardiac diseases and three controls. Second, we differentiated human iPSCs derived from patients with Timothy syndrome into cardiomyocytes using a monolayer differentiation method. We found that Timothy syndrome cardiomyocytes showed slower, irregular contractions and abnormal calcium handling compared with the controls. The results are consistent with previous reports using a retroviral method for reprogramming and an embryoid body-based method for cardiac differentiation. Third, we developed an efficient approach for recording the action potentials and calcium transients simultaneously in control and patient cardiomyocytes using genetically encoded fluorescent indicators, ArcLight and R-GECO1. The dual optical recordings enabled us to observe prolonged action potentials and abnormal calcium handling in Timothy syndrome cardiomyocytes. We confirmed that roscovitine rescued the phenotypes in Timothy syndrome cardiomyocytes and that these findings were consistent with previous studies using conventional electrophysiological recordings and calcium imaging with dyes. The approaches using our optimized methods and dual optical recordings will improve iPSC applicability for disease modeling to investigate mechanisms underlying cardiac arrhythmias and to test potential therapeutics.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>This study found that dual optical recording using genetically encoded fluorescent indicators is a useful approach for identifying new lead chemical compounds in human induced pluripotent stem (iPS) cell-based models of not only cardiac diseases but also neuronal disorders. It will facilitate drug development and personalized medicine using iPS technology.<\/jats:p>\n               <\/jats:sec>","DOI":"10.5966\/sctm.2014-0245","type":"journal-article","created":{"date-parts":[[2015,3,14]],"date-time":"2015-03-14T02:12:34Z","timestamp":1426299154000},"page":"468-475","source":"Crossref","is-referenced-by-count":39,"title":["Dual Optical Recordings for Action Potentials and Calcium Handling in Induced Pluripotent Stem Cell Models of Cardiac Arrhythmias Using Genetically Encoded Fluorescent Indicators"],"prefix":"10.1093","volume":"4","author":[{"given":"LouJin","family":"Song","sequence":"first","affiliation":[{"name":"Columbia University Stem Cell Initiative, Columbia University, New York, New York, USA"},{"name":"Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, New York, USA"},{"name":"Department of Pharmacology, Columbia University, New York, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel W.","family":"Awari","sequence":"additional","affiliation":[{"name":"Columbia University Stem Cell Initiative, Columbia University, New York, New York, USA"},{"name":"Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth Y.","family":"Han","sequence":"additional","affiliation":[{"name":"Columbia University Stem Cell Initiative, Columbia University, New York, New York, USA"},{"name":"Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, New York, USA"},{"name":"Barnard College, New York, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugenia","family":"Uche-Anya","sequence":"additional","affiliation":[{"name":"Columbia University Stem Cell Initiative, Columbia University, New York, New York, USA"},{"name":"Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, New York, USA"},{"name":"College of Physicians and Surgeons, Columbia University, New York, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seon-Hye E.","family":"Park","sequence":"additional","affiliation":[{"name":"Columbia University Stem Cell Initiative, Columbia University, New York, New York, USA"},{"name":"Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoko A.","family":"Yabe","sequence":"additional","affiliation":[{"name":"Columbia University Stem Cell Initiative, Columbia University, New York, New York, USA"},{"name":"Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy K.","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Medicine, Columbia University, New York, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Yazawa","sequence":"additional","affiliation":[{"name":"Columbia University Stem Cell Initiative, Columbia University, New York, New York, USA"},{"name":"Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, New York, USA"},{"name":"Department of Pharmacology, Columbia University, New York, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,3,13]]},"reference":[{"key":"2021122704234089300_R1","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1056\/NEJMoa0908679","article-title":"Patient-specific induced pluripotent stem-cell models for long-QT syndrome","volume":"363","author":"Moretti","year":"2010","journal-title":"N Engl J 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human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome","volume":"32","author":"Bellin","year":"2013","journal-title":"EMBO J"},{"key":"2021122704234089300_R6","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.neuron.2012.06.040","article-title":"Single action potentials and subthreshold electrical events imaged in neurons with a fluorescent protein voltage probe","volume":"75","author":"Jin","year":"2012","journal-title":"Neuron"},{"key":"2021122704234089300_R7","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1126\/science.1208592","article-title":"An expanded palette of genetically encoded Ca2+ indicators","volume":"333","author":"Zhao","year":"2011","journal-title":"Science"},{"key":"2021122704234089300_R8","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/nmeth.1593","article-title":"Chemically defined conditions for human iPSC derivation and 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