Engineered cocultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation

• DOI: 10.1126/sciadv.adg1222
• Publication Date: 2024-01-19T18:58:32Z
• Authors: Grace E. Brown; Yong Duk Han; Ashlin R. Michell; Olivia T. Ly; Carlos G. Vanoye; Emanuele Spanghero; Alfred L. George; Dawood Darbar; Salman R. Khetani
• Keywords: Adult; 0303 health sciences; 03 medical and health sciences; Atrial Fibrillation; Induced Pluripotent Stem Cells; Humans; Myocytes, Cardiac; Biomedicine and Life Sciences; Fibroblasts; Coculture Techniques

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia treatable with antiarrhythmic drugs; however, patient responses remain highly variable. Human induced pluripotent stem cell–derived atrial cardiomyocytes (iPSC-aCMs) are useful for discovering precision therapeutics, but current platforms yield phenotypically immature cells and are not easily scalable for high-throughput screening. Here, primary adult atrial, but not ventricular, fibroblasts induced greater functional iPSC-aCM maturation, partly through connexin-40 and ephrin-B1 signaling. We developed a protein patterning process within multiwell plates to engineer patterned iPSC-aCM and atrial fibroblast coculture (PC) that significantly enhanced iPSC-aCM structural, electrical, contractile, and metabolic maturation for 6+ weeks compared to conventional mono-/coculture. PC displayed greater sensitivity for detecting drug efficacy than monoculture and enabled the modeling and pharmacological or gene editing treatment of an AF-like electrophysiological phenotype due to a mutated sodium channel. Overall, PC is useful for elucidating cell signaling in the atria, drug screening, and modeling AF.