Key result
Expression of BIN1 in human embryonic stem cell-derived cardiomyocytes induced T-tubule development, increased CaV1.2 channel clustering, and enhanced excitation-contraction coupling.
Why the study?
Does BIN1 expression induce T-tubule formation and CaV1.2 channel clustering in human embryonic stem cell-derived cardiomyocytes?
Does BIN1 expression induce T-tubule formation and CaV1.2 channel clustering in human embryonic stem cell-derived cardiomyocytes?
BIN1 is a key regulator of T-tubule formation, CaV1.2 channel clustering, and excitation-contraction coupling in developing human embryonic stem cell-derived cardiomyocytes.
May support BIN1 for T-tubule maturation in stem-cell models; leaves open clinical translation to cardiac regeneration.
Human 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 CaV1.2 channel clustering along the tubules, and results in the development of stable CRUs. Using electrophysiology, [Ca2+]i 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 CaV1.2 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 CaV1.2 clusters grew, as BIN1 expression increased and cells matured. BIN1 expression increased CaV1.2 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 CaV1.2-ryanodine receptor junctions than control cells. This was associated with larger [Ca2+]i transients during excitation–contraction coupling. Our data support the view that BIN1 is a key regulator of T-tubule formation and CaV1.2 channel delivery. By studying the role of BIN1 during the differentiation of hESC-CMs, we show that BIN1 is also important for CaV1.2 channel clustering, junctional SR organization, and the establishment of excitation–contraction coupling. Stem Cells 2019;37:54–64
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Mata et al. (2018) studied Cardiac cell development. BIN1 expression vs. Control cells was evaluated on T-tubule development, CaV1.2 channel clustering, and excitation-contraction coupling. Expression of BIN1 in human embryonic stem cell-derived cardiomyocytes induced T-tubule development, increased CaV1.2 channel clustering, and enhanced excitation-contraction coupling.
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