Biology subjects

Tsui, J. H.

Publications and source records attributed to Tsui, J. H..

3 recordsLinked to original sources

bioRxiv2025

SYNPO2L Isoforms Regulate the Action Potential Characteristics and Contractility of Atrial Cardiomyocytes via YAP Signaling to Modulate Atrial Fibrillation Risk

BackgroundSYNPO2L is a component of the sarcomere Z-disk with two distinct isoforms (SYNPO2L_A and SYNPO2L_B) described to regulate actin bundle size. Common and rare variations in SYNPO2L have been implicated in risk for heart failure and atrial fibrillation (AF); however, little is known about the function or pathophysiological mechanism upon disease risk. MethodsThe role of SYNPO2L was explored with human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) models of a rare splicing mutation rs766868752 differentiated into both atrial and ventricular lineages. Electrophysiology was assessed via multi-electrode arrays (MEAs) and contractility was assessed using engineered heart tissues (EHTs). Genetic survival analyses were performed to explore the potential therapeutic role of the SYNPO2L_A isoform in AF risk after myocardial infarction. ResultshiPSC-CMs carrying the splice mutation rs766868752 resulted in preferential expression of the SYNPO2L_B isoform and absence of SYNPO2L_A isoform, and atrial hiPSC-CMs displayed significant differences in action potential durations when unpaced, and spontaneous extra-systolic beats when paced. Contractility of atrial hiPSC-CMs carrying the splice mutation was severely compromised. Electrophysiological differences were normalized and contractility was partially restored by overexpression with AAV:SYNPO2L_A. Absence of SYNPO2L_A in the mutant led to an observed decreased phosphorylation of YAP along with significant downstream transcriptional effects. A direct interaction between SYNPO2L_A and LATS2, a known regulator of YAP phosphorylation was found to occur in hiPSC-CMs. Additionally, a common variant time-to-event analysis may suggest a beneficial effect of the SYNPO2L_A isoform to lower the risk of atrial fibrillation after myocardial infarction. ConclusionsA rare splice mutation conferring isoform predominance of SYNPO2L_B appears to disturb the electrophysiology and contractility of atrial hiPSC-CMs via LATS2 phospho-regulatory effects upon YAP signaling. Supplementation of the SYNPO2L_A isoform can restore many functional deficits and supports a specific gene regulatory role for SYNPO2L in modulating the risk of AF and heart failure.

cell biology↗

bioRxiv2022

Perpendicular Shear Stresses Drive Transmural Helical Remodeling in Engineered Human Ventricular Models

Tissue engineering with human induced pluripotent stem cell-derived cardiomyocytes enables unique opportunities for creating physiological models of the heart in vitro. However, there are few approaches available that can recapitulate the complex structure-function relationships that govern cardiac function at the macroscopic organ level. Here, we report a down-scaled, conical human 3D ventricular model with controllable cellular organization using multilayered, patterned cardiac sheets. Tissue engineered ventricles whose cardiomyocytes were pre-aligned parallel or perpendicular to the long axis outperformed those whose cardiomyocytes were angled or randomly oriented. Notably, the inner layers of perpendicular cardiac sheets realigned over 4 days into a parallel orientation, creating a helical transmural architecture, whereas minimal remodeling occurred in the parallel or angled sheets. Finite element analysis of engineered ventricles demonstrated that circumferential alignment leads to maximal perpendicular shear stress at the inner layer, whereas longitudinal orientation leads to maximal parallel stress. We hypothesize that cellular remodeling occurs to reduce perpendicular shear stresses in myocardium. This advanced platform provides evidence that physical forces such as shear stress drive self-organization of cardiac architecture.

bioengineering↗

bioRxiv2019

Functional Maturation of Human iPSC-based Cardiac Microphysiological Systems with Tunable Electroconductive Decellularized Extracellular Matrices

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer tremendous potential for use in engineering human tissues for regenerative therapy and drug screening. However, differentiated cardiomyocytes are phenotypically immature, reducing assay reliability when translating in vitro results to clinical studies and precluding hiPSC-derived cardiac tissues from therapeutic use in vivo. To address this, we have developed hybrid hydrogels comprised of decellularized porcine myocardial extracellular matrix (dECM) and reduced graphene oxide (rGO) to provide a more instructive microenvironment for proper cellular and tissue development. A tissue-specific protein profile was preserved post-decellularization, and through the modulation of rGO content and degree of reduction, the mechanical and electrical properties of the hydrogels could be tuned. Engineered heart tissues (EHTs) generated using dECM-rGO hydrogel scaffolds and hiPSC-derived cardiomyocytes exhibited significantly increased twitch forces at 14 days of culture and had increased the expression of genes that regulate contractile function. Similar improvements in various aspects of electrophysiological function, such as calcium-handling, action potential duration, and conduction velocity, were also induced by the hybrid biomaterial. We also demonstrate that dECM-rGO hydrogels can be used as a bioink to print cardiac tissues in a high-throughput manner, and these tissues were utilized to assess the proarrhythmic potential of cisapride. Action potential prolongation and beat interval irregularities was observed in dECM-rGO tissues at clinical doses of cisapride, indicating that the enhanced maturation of these tissues corresponded well with a capability to produce physiologically relevant drug responses.

bioengineering↗