iPS-ChOp-AF

Cardiac arrhythmias are responsible for significant morbidity and mortality. However, the study and treatment of these rhythm disorders have been hampered by the lack of relevant human cardiac tissue models, specifically those reflecting patient/disease-specific abnormalities, by paucity of methods for long-term electrophysiological analysis of the tissue, and by the inability to perform targeted, high-resolution, reversible, and functional perturbations of the system.

To address these challenges, we combined human induced pluripotent stem cells (hiPSC) and genome-editing (CRISPR) technologies, developmental biology-inspired differentiating systems that yield chamber-specific heart cells, novel tissue engineering strategies, and emerging concepts from the fields of optogenetics and chemogenetics. The resulting experimental models represent major progress in the way we study and cardiac arrhythmias and offer potential insights into how we may treat them. To demonstrate the unique potential of this approach, we conducted and published multiple studies in which we:

1. Developed patient/disease-specific hiPSC models of genetic atrial fibrillation (AF) and established hiPSC differentiation protocols to yield purified atrial cells.

2. Utilized the hiPSC-atrial cells and advanced tissue-engineering strategies (hydrogels, 3D printing, decellularization) to establish 2D cell-sheet and 3D tissue models of acquired and inherited AF, in which functional re-entry ("rotors") could be studied.

3. Utilized tools from optogenetics (light-sensitive ion channels and pumps) and chemogenetics (ligand-specific engineered receptors) for targeted manipulation of the system, to gain insights into arrhythmia pathogenesis and to develop novel therapies

4. Evaluated the developed optogenetic and chemogenetic treatments in animal models
The results of this project should provide novel mechanistic insights into AF (and other arrhythmias) and open the road for the development of novel therapeutic paradigms.