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dc.contributor.authorDe La Mata Sampedro, Ana 
dc.contributor.authorTajada, Sendoa
dc.contributor.authorO'Dwyer, Samantha
dc.contributor.authorMatsumoto, Collin
dc.contributor.authorDixon, Rose E.
dc.contributor.authorHariharan, Nirmala
dc.contributor.authorMoreno, Claudia M.
dc.contributor.authorSantana, Luis Fernando
dc.date.accessioned2024-01-12T12:35:50Z
dc.date.available2024-01-12T12:35:50Z
dc.date.issued2019
dc.identifier.citationStem Cells. 2019 Jan;37(1):54-64. doi: 10.1002/stem.2927. Epub 2018 Nov 22. PMID: 30353632; PMCID: PMC6312737.es
dc.identifier.issn1066-5099es
dc.identifier.urihttps://uvadoc.uva.es/handle/10324/64481
dc.description.abstractHuman embryonic stem cell-derived cardiomyocytes (hESC-CMs) are at the center of new cell-based therapies for cardiac disease, but may also serve as a useful in vitro model for cardiac cell development. An intriguing feature of hESC-CMs is that although they express contractile proteins and have sarcomeres, they do not develop transverse-tubules (T-tubules) with adult-like Ca2+ release units (CRUs). We tested the hypothesis that expression of the protein BIN1 in hESC-CMs promotes T-tubules formation, facilitates CaV 1.2 channel clustering along the tubules, and results in the development of stable CRUs. Using electrophysiology, [Ca2+ ] imaging, and super resolution microscopy, we found that BIN1 expression induced T-tubule development in hESC-CMs, while increasing differentiation toward a more ventricular-like phenotype. Voltage-gated CaV 1.2 channels clustered along the surface sarcolemma and T-tubules of hESC-CM. The length and width of the T-tubules as well as the expression and size of CaV 1.2 clusters grew, as BIN1 expression increased and cells matured. BIN1 expression increased CaV 1.2 channel activity and the probability of coupled gating within channel clusters. Interestingly, BIN1 clusters also served as sites for sarcoplasmic reticulum (SR) anchoring and stabilization. Accordingly, BIN1-expressing cells had more CaV 1.2-ryanodine receptor junctions than control cells. This was associated with larger [Ca2+ ] transients during excitation-contraction coupling. Our data support the view that BIN1 is a key regulator of T-tubule formation and CaV 1.2 channel delivery. By studying the role of BIN1 during the differentiation of hESC-CMs, we show that BIN1 is also important for CaV 1.2 channel clustering, junctional SR organization, and the establishment of excitation-contraction couplinges
dc.format.mimetypeapplication/pdfes
dc.language.isoenges
dc.publisherWiley Periodicalses
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses
dc.rights.urihttp://creativecommons.org/publicdomain/zero/1.0/*
dc.titleBIN1 Induces the Formation of T-Tubules and Adult-Like Ca2+ Release Units in Developing Cardiomyocyteses
dc.typeinfo:eu-repo/semantics/articlees
dc.identifier.doi10.1002/stem.2927es
dc.identifier.publicationfirstpage54es
dc.identifier.publicationissue1es
dc.identifier.publicationlastpage64es
dc.identifier.publicationtitleStem Cellses
dc.identifier.publicationvolume37es
dc.peerreviewedSIes
dc.identifier.essn1549-4918es
dc.rightsCC0 1.0 Universal*
dc.type.hasVersioninfo:eu-repo/semantics/draftes


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