Pozo, M. R. | Search bioRxiv

bioRxiv2026

Comparative transcriptomics analysis of histone deacetylases, transcription factors, and ion channel genes in human iPSC-cardiomyocytes vs. the adult human heart

Epigenetic modulators such as histone deacetylases (HDACs) and histone acetyltransferases (HATs) are known master regulators of gene expression that substantially impact cardiac electrophysiology. Novel pharmacological agents, HDAC inhibitors, are rapidly emerging as treatments for cancer and immune diseases, and their effects on cardiac ion channels (ICs) are of great interest. We used small interfering RNAs to individually suppress each of the known HDACs, including sirtuins (SIRTs), in human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs), iCell2. Follow-up deep-sequencing allowed comparison to identically processed and normalized RNA sequencing data from adult human left ventricle (LV) from the GTEx database. The transcriptomics analysis revealed high similarity of gene expression patterns for cardiac ICs (with some differences in calcium influx and calcium buffering related genes), as well as strong co-regulation by cardiac transcription factors (TFs) and HDACs/SIRTs in both hiPSC-CMs and the adult LV. Partial least square regression models helped visualize links between HDACs/HATs, TFs, and cardiac ICs and helped identify potential key regulators of cardiac IC transcription. Powerful TFs, including MEF2A, GATA4, 6 exerted positive effect on IC genes while RUNX1 and SHMT2 were distinct negative regulators in both sample types; TRIM28 was found to serve opposite roles in the two sample types. In functional measurements, HDAC suppression primarily increased excitability, while SIRT suppression decreased excitability, in line with transcriptomic links. Our analysis offers insights about the role of epigenetic modifiers in regulating cardiac electrophysiology and informs the utility of hiPSC-CM as a scalable experimental model for cardiotoxicity testing of HDAC inhibitors.

bioengineering↗

bioRxiv2024

Control of electromechanical waves in engineered tissue of human iPSC-cardiomyocytes using a Halbach array and magnetic nanoparticles

The Halbach array, originally developed for particle accelerators, is a compact arrangement of permanent magnets to create well-defined magnetic fields without heating. Here, we demonstrate its use for modulating the speed of electromechanical waves in cardiac syncytia of human stem cell-derived cardiomyocytes. At 40-50 mT magnetic field strength, a cylindrical dipolar Halbach array boosted the conduction velocity, CV, of excitation in a directional manner by up to 25% when the magnetic field was co-aligned with the electromechanical wave (but not when perpendicular to it). To observe the effects, a short-term incubation of the cardiac cell constructs with non-targeted magnetic nanoparticles, mNPs, was sufficient. This increased CV anisotropy, and the effects were most pronounced at slower pacing rates. Instantaneous formation and re-arrangement of elongated mNP clusters upon magnetic field rotation was seen, thus creating dynamic structural anisotropy that may have contributed to the directional CV effects. This approach may be useful for anti-arrhythmic control of cardiac waves. One sentence summaryA Halbach array of permanent magnets can modulate the speed of excitation waves in human cardiac cell assemblies with magnetic nanoparticles.

bioengineering↗