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University of Illinois at Chicago

Sci. Adv., Jan 19 2024, 10 (3) eadg1222 | https://doi.org/10.1126/sciadv.adg1222 Engineered cocultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation

Grace E Brown^{1 †}, Yong Duk Han^{1 †}, Ashlin R Michell ¹, Olivia T Ly ^{1 2}, Carlos G Vanoye ³, Emanuele Spanghero ¹, Alfred L George Jr ³, Dawood Darbar ^{1 2 4 5 *}, Salman R Khetani ^{1 *}

¹Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL, USA.

²Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

³Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

⁴Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA.

⁵Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, USA.

^†These authors contributed equally
^*Corresponding authors: correspondence to Dawood Darbar or Salman R Khetani

Abstract

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.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-02-26)
연구진국외 연구진
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