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Purpose <p>Myocardial infarction results in extensive cardiac remodeling that can lead to heart failure. Human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) injection can improve heart function but may lead to engraftment-associated ventricular tachycardia (VT). Optogenetics uses light stimulation to control electrical activity of cells genetically modified to express light-sensitive proteins (opsins). This study aims to use computational simulations to test the feasibility of optogenetically suppressing hPSC-CM ectopic activity without inhibiting the ability to undergo excitation by upstream wavefronts (i.e., engrafted cells could activate harmoniously with surrounding host myocardium during propagation of a normal sinus beat).</p> Methods <p>We simulated electrophysiology in single-cell hPSC-CM and tissue-scale ventricular models derived from histology images. The latter comprised host myocardium, hPSC-CM graft, and non-conductive scar. Ventricular and hPSC-CM cellular models were used in the host myocardium and hPSC-CM graft regions, respectively. Optogenetic modification of hPSC-CMs was simulated via incorporation of a photocycle model with the approximate properties of WiChR, a light-sensitive potassium channel. To test the efficacy of the proposed approach for silencing graft activity, we simulated sustained blue light illumination at 488&#xa0;nm.</p> Results <p>Sustained optogenetic stimulation suppressed spontaneous excitation altogether in opsin-expressing hPSC-CM models while maintaining cellular excitability. At the tissue scale, optogenetic suppression of VT-associated ectopic excitations was feasible with epicardial illumination. Opsin-expressing grafts in optogenetically silenced histology models remained excitable under simulated sinus rhythm-like excitation from the endocardium; however, potentially arrhythmogenic spatial heterogeneity of action potential duration was seen in model geometries with greater wall thickness.</p> Conclusions <p>Our simulations suggest WiChR-based optogenetic suppression of hPSC-CM graft-associated arrhythmia is likely feasible but must be carefully calibrated to avoid inadvertently pro-arrhythmic side effects.</p>

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Computational Simulations Show Proof-of-Concept for Optogenetic Suppression of Ectopic Activity in Cardiac Stem Cell Therapy

  • 期刊论文

  • 发表日期：

    2025年7月16日

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  • Jamie S. Yang,
  • Alexander R. Ochs,
  • Chelsea E. Gibbs,
  • Patrick M. Boyle

摘要

Purpose

Myocardial infarction results in extensive cardiac remodeling that can lead to heart failure. Human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) injection can improve heart function but may lead to engraftment-associated ventricular tachycardia (VT). Optogenetics uses light stimulation to control electrical activity of cells genetically modified to express light-sensitive proteins (opsins). This study aims to use computational simulations to test the feasibility of optogenetically suppressing hPSC-CM ectopic activity without inhibiting the ability to undergo excitation by upstream wavefronts (i.e., engrafted cells could activate harmoniously with surrounding host myocardium during propagation of a normal sinus beat).

Methods

We simulated electrophysiology in single-cell hPSC-CM and tissue-scale ventricular models derived from histology images. The latter comprised host myocardium, hPSC-CM graft, and non-conductive scar. Ventricular and hPSC-CM cellular models were used in the host myocardium and hPSC-CM graft regions, respectively. Optogenetic modification of hPSC-CMs was simulated via incorporation of a photocycle model with the approximate properties of WiChR, a light-sensitive potassium channel. To test the efficacy of the proposed approach for silencing graft activity, we simulated sustained blue light illumination at 488 nm.

Results

Sustained optogenetic stimulation suppressed spontaneous excitation altogether in opsin-expressing hPSC-CM models while maintaining cellular excitability. At the tissue scale, optogenetic suppression of VT-associated ectopic excitations was feasible with epicardial illumination. Opsin-expressing grafts in optogenetically silenced histology models remained excitable under simulated sinus rhythm-like excitation from the endocardium; however, potentially arrhythmogenic spatial heterogeneity of action potential duration was seen in model geometries with greater wall thickness.

Conclusions

Our simulations suggest WiChR-based optogenetic suppression of hPSC-CM graft-associated arrhythmia is likely feasible but must be carefully calibrated to avoid inadvertently pro-arrhythmic side effects.