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.
| Original language | English (US) |
|---|---|
| Journal | Science Advances |
| Volume | 10 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2024 |
Funding
the Scn5A 1043 and 1041 lines were generated by the Stanford Cardiovascular Institute. this work made use of instruments in the electron Microscopy core of Uic’s Research Resources Center. We would like to thank P. Faber and M. nuenningoff from The University of Chicago core Genomics Facility for assistance with RnA-seq. We would also like to thank c. castella for assistance with cell culture. this work was supported by the National Institutes of Health grants R01 hl150586 (to d.d., SRK), R01 hl148444 (to d.d.), vA Merit Review 1iO1BX004268 (to d.d.) and t32 hl139439 (to d.d.) and Veterans Administration Merit Review 1iO1BX004268 (to d.d.).
ASJC Scopus subject areas
- General