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Perhaps contributing to this situation, hPSC-CM grafts show low expression of connexin 43 (Cx43), the major gap junction (GJ) protein, in ventricular myocardia. We hypothesized that Cx43 expression and function could be rescued by engineering Cx43 in hPSC-CMs with a series of phosphatase-resistant mutations at three casein kinase 1 phosphorylation sites (Cx43-S3E) that have been previously reported to stabilize Cx43 GJs and reduce arrhythmias in transgenic mice. However, contrary to our predictions, transgenic Cx43-S3E hPSC-CMs exhibited reduced Cx43 expression relative to wild-type cells, both at baseline and following ischemic challenge. Cx43-S3E hPSC-CMs showed correspondingly slower conduction velocities, increased automaticity, and differential expression of other connexin isoforms and various genes involved in cardiac excitation\u2013contraction coupling. Cx43-S3E hPSC-CMs also had phosphorylation marks associated with Cx43 GJ internalization, a finding that may account for their impaired GJ localization. Taken collectively, our data indicate that the Cx43-S3E mutation behaves differently in hPSC-CMs than in adult mouse ventricular myocytes and that multiple biological factors likely need to be addressed synchronously to ensure proper Cx43 expression, localization, and function.<\/jats:p>","DOI":"10.3390\/biom14010061","type":"journal-article","created":{"date-parts":[[2024,1,2]],"date-time":"2024-01-02T10:36:59Z","timestamp":1704191819000},"page":"61","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Casein Kinase 1 Phosphomimetic Mutations Negatively Impact Connexin-43 Gap Junctions in Human Pluripotent Stem Cell-Derived Cardiomyocytes"],"prefix":"10.3390","volume":"14","author":[{"given":"Rasha","family":"Al-attar","sequence":"first","affiliation":[{"name":"McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Jargstorf","sequence":"additional","affiliation":[{"name":"McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocco","family":"Romagnuolo","sequence":"additional","affiliation":[{"name":"McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Jouni","sequence":"additional","affiliation":[{"name":"McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faisal J.","family":"Alibhai","sequence":"additional","affiliation":[{"name":"McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1399-2761","authenticated-orcid":false,"given":"Paul D.","family":"Lampe","sequence":"additional","affiliation":[{"name":"Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joell L.","family":"Solan","sequence":"additional","affiliation":[{"name":"Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Laflamme","sequence":"additional","affiliation":[{"name":"McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada"},{"name":"Peter Munk Cardiac Centre, University Health Network, Toronto, ON M5G 1L7, Canada"},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/nature10147","article-title":"Heart Regeneration","volume":"473","author":"Laflamme","year":"2011","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/nature11317","article-title":"Human ES-Cell-Derived Cardiomyocytes Electrically Couple and Suppress Arrhythmias in Injured Hearts","volume":"489","author":"Shiba","year":"2012","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1177\/1074248413520344","article-title":"Electrical Integration of Human Embryonic Stem Cell-Derived Cardiomyocytes in a Guinea Pig Chronic Infarct Model","volume":"19","author":"Shiba","year":"2014","journal-title":"J. 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