Thyroid and Glucocorticoid Hormones Promote Functional T-Tubule Development in Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes

Parikh, Shan; Blackwell, Daniel J.; Gómez-Hurtado, Nieves; Frisk, Michael; Wang, Lili; Kim, Kyung-Soo; Dahl, Christen P.; Fiane, Arnt E.; Tønnessen, Theis; Kryshtal, Dmytro O.; Louch, William E.; Knollmann, Björn C.

doi:10.1161/circresaha.117.311920

Cited by 293 publications

(210 citation statements)

References 25 publications

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“…Indeed, as we prepared the current manuscript for publication, another study looking at T-tubule biogenesis but in human-induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) was published. In this study, Parikh et al [44] demonstrated that hiPSC-CMs develop T-tubules when exposed to thyroid and glucocorticoid hormones during differentiation. This was not associated with an increase in BIN1 expression, suggesting a BIN1-independndent mechanism for T-tubular formation.…”

Section: Discussionmentioning

confidence: 63%

BIN1 Induces the Formation of T-Tubules and Adult-Like Ca2+ Release Units in Developing Cardiomyocytes

et al. 2018

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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 towards 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 EC coupling.

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Section: Discussionmentioning

confidence: 63%

BIN1 Induces the Formation of T-Tubules and Adult-Like Ca2+ Release Units in Developing Cardiomyocytes

et al. 2018

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“…To achieve higher degrees of CM maturation and function, a variety of methods have been developed, including dynamic culture 5 , three-dimensional (3D) engineered heart tissue 6,7 , 3D printing 8 , addition of factors 9 , extracellular matrix 9,10 , and external stimulation. Electrical stimulation, especially high-frequency pacing, has long been suggested as an effective method for maturing muscle cells 11–14 , which upregulates cardiac markers 12,13,15 , enhances Ca 2+ -handling properties 3 , and promotes CM alignment 16 .…”

Section: Introductionmentioning

confidence: 99%

Rapid pacing by circulating traveling waves improves maturation of hiPSC-derived cardiomyocytes in self-organized tissue ring

Zhang

et al. 2019

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30Directed differentiation methods allow acquisition of high-purity cardiomyocytes (CMs) 31 differentiated from human induced pluripotent stem cells (hiPSCs); however, their 32 immaturity characteristic limits their application for drug screening and regenerative therapy. 33 The rapid electrical pacing of cardiomyocytes have been used for efficiently promoting the 34 maturation of cardiomyocytes, here we describe a simple device in modified culture plate on 35 which hiPSC-derived CMs (hiPSC-CMs) can form three-dimensional self-organized tissue 36 rings (SOTRs). Using calcium imaging, we show that within the ring, traveling waves (TWs) 37 of action potential spontaneously originated and ran robustly at a frequency up to 4 Hz. After 38 2 weeks, SOTRs with TW training showed matured features including structural organization, 39 increased cardiac-specific gene expression, enhanced Ca 2+ -handling properties, an increased 40 oxygen-consumption rate, and enhanced contractile force. We subsequently used a 41 mathematical model to interpret the origination, propagation, and long-term behavior of the 42 TWs within the SOTRs. This new idea for spontaneous hiPSC-CM maturation also has 43 potential for pacing the electrical excitable cells such as neuron and retina cells for various 44 applications. 45 46 47 48

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“…A stable T‐tubule microanatomy is an indispensable factor for the clustering of LTCCs and structuring of the dyads with the SR membrane (see Figure ). Another research on hiPSC‐CM suggests a role of combined thyroid and glucocorticoid hormones during the cardiac differentiation process which, when coupled with further maturation on Matrigel mattress, is sufficient for T‐tubule development, enhanced CICR and more ventricular‐like EC coupling . cBIN1‐related regulatory mechanisms are not yet available, and further studies about the interaction between cBIN1 and related hormones in cardiomyocytes are needed.…”

Section: Effect Of Bin1 On Cardiac Contractionmentioning

confidence: 99%

Effect of BIN1 on cardiac dysfunction and malignant arrhythmias

et al. 2019

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Heart failure (HF) is the end‐stage syndrome for most cardiac diseases, and the 5‐year morbidity and mortality of HF remain high. Malignant arrhythmia is the main cause of sudden death in the progression of HF. Recently, bridging integrator 1 (BIN1) was discovered as a regulator of transverse tubule function and calcium signalling in cardiomyocytes. BIN1 downregulation is linked to abnormal cardiac contraction, and it increases the possibility of malignant arrhythmias preceding HF. Because of the detectability of cardiac BIN1 in peripheral blood, BIN1 may serve as a predictor of HF and may be useful in therapy development. However, the mechanism of BIN1 downregulation in HF and how BIN1 regulates normal cardiac function under physiological conditions remain unclear. In this review, recent progress in the biological studies of BIN1‐related cardiomyocytes and the effect of cardiac dysfunction and malignant arrhythmia will be discussed.

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Thyroid and Glucocorticoid Hormones Promote Functional T-Tubule Development in Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes

Cited by 293 publications

References 25 publications

BIN1 Induces the Formation of T-Tubules and Adult-Like Ca2+ Release Units in Developing Cardiomyocytes

BIN1 Induces the Formation of T-Tubules and Adult-Like Ca2+ Release Units in Developing Cardiomyocytes

Rapid pacing by circulating traveling waves improves maturation of hiPSC-derived cardiomyocytes in self-organized tissue ring

Effect of BIN1 on cardiac dysfunction and malignant arrhythmias

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