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Engineered co-cultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation [I]

ABSTRACT: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia treatable with antiarrhythmic drugs, but patient responses are highly variable. Human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) are useful for discovering precision therapeutics, but current platforms yield an immature cellular phenotype and are not easily scalable for high-throughput screening. Here, we report that 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 industry-standard multiwell plates to engineer patterned co-culture (PC) of iPSC-aCMs and atrial fibroblasts that significantly enhanced iPSC-aCM structural, electrical, contractile, and metabolic maturation for 6+ weeks versus conventional mono-/co-cultures. PC displayed greater sensitivity for detecting drug efficacy than monocultures, and enabled the modeling and pharmacological or gene editing treatment of an AF-like electrophysiological phenotype due to a sodium channel mutation. In conclusion, PC is useful to elucidate heterotypic cell signaling in the atria, drug screening, and to model AF.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239317 | GEO | 2024/01/19

REPOSITORIES: GEO

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Project description:Atrial fibrillation (AF) has an estimated prevalence of 1.5–2%, making it the most common cardiac arrhythmia. The mechanisms that cause and sustain AF are still not completely understood. An association between AF and systemic as well as local inflammatory processes has been reported, however, the exact mechanisms underlying this association have not been established. While it is understood that tissue resident macrophages can influence cardiac electrophysiology, the effects of activated pro-inflammatory macrophages have not been described yet. This study investigated the pro-arrhythmic effects of activated macrophages (M1) on human induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes (aCM), to propose a mechanistic link between inflammation and AF. Two hiPSC lines from healthy individuals were differentiated to aCMs and M1 macrophages. Electrophysiology characteristics of M1 and aCM cocultures were analysed for beat rate irregularity, electrogram amplitude and conduction velocity. M1 cocultures resulted in a significant increase in beat rate irregularity and decrease in electrogram amplitude compared to other conditions tested, including aCMs treated with activated M1 supernatant, which did not produce an increase in irregularity. Conduction analysis further showed significantly lower conduction homogeneity in M1 cocultures. Immunosuppression through glucocorticoids significantly decreased beat irregularity in aCM+M1 cocultures compared to vehicle. RNA sequencing performed in aCMs, revealed downregulation of various ion channels (SCNA5, KCNA5, ATP1A1), as a result of the M1 coculture. Electrophysiology related transcription changes were reversed by glucocorticoid treatment. This study establishes a causal relationship between M1 activation and the development of subsequent atrial arrhythmia, documented as irregularity in spontaneous electrical activation in aCM cocultured with activated macrophages. Further, beat rate irregularity could be alleviated using anti-inflammatory steroidal glucocorticoids. These results strongly support the relevance of the proposed hiPSC-derived coculture model and point at macrophage mediated inflammation as a potential AF mechanism.

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Engineered co-cultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation [I]

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