Bioengineering approaches to mature induced pluripotent stem cell-derived atrial cardiomyocytes to model atrial fibrillation

Abstract

Induced pluripotent stem cells (iPSCs) serve as a robust platform to model several human arrhythmia syndromes including atrial fibrillation (AF). However, the structural, molecular, functional, and electrophysiological parameters of patient-specific iPSC-derived atrial cardiomyocytes (iPSC-aCMs) do not fully recapitulate the mature phenotype of their human adult counterparts. The use of physiologically inspired microenvironmental cues, such as postnatal factors, metabolic conditioning, extracellular matrix (ECM) modulation, electrical and mechanical stimulation, co-culture with non-parenchymal cells, and 3D culture techniques can help mimic natural atrial development and induce a more mature adult phenotype in iPSC-aCMs. Such advances will not only elucidate the underlying pathophysiological mechanisms of AF, but also identify and assess novel mechanism-based therapies towards supporting a more ‘personalized’ (i.e. patient-specific) approach to pharmacologic therapy of AF.

Mutant ANP induces mitochondrial and ion channel remodeling in a human iPSC–derived atrial fibrillation model

“…Modeling rare mutations in familial AF kindred using immature iPSC-aCMs has provided some insights into the underlying pathophysiology of AF and identified patient-specific mechanisms (16,38). However, with the advent of advanced engineering techniques to further mature iPSC-aCMs, we predict that all future studies modeling genetic variants associated with AF will use mature iPSC-aCMs (39). Currently, pharmacological response to antiarrhythmic therapy is highly variable because of incomplete understanding of the pathophysiological mechanisms and our inability to predict responses in individual patients (40).…”

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

“…Despite recent advances in catheter-based therapies, antiarrhythmic drugs (AADs) are still often used to treat symptomatic AF. However, the response in an individual patient is highly variable with ~50% of patients experiencing AF recurrence within 6 months of treatment ( 4 ). The lack of AAD efficacy is, in part, due to the inability to target the underlying and often unknown genetic mechanisms of AF ( 5 ) given the paucity of model systems.…”

“…However, current differentiation protocols lead to immature iPSC-aCMs ( 7 , 8 ) that do not faithfully recapitulate an AF susceptible cellular substrate. Therefore, there is a critical need to develop improved maturation strategies for iPSC-aCMs with the goals of elucidating the key genetic determinants of AF and developing precision therapeutics ( 4 ).…”

Functional Activity of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes on a Mouse Renal Subcapsular Xenograft Model

“…Ideally, for myocardial repair, iPSC-derived cardiomyocytes should exhibit electrical and mechanical properties that closely resemble those of native myocardium [ 11 ]. It is anticipated that such mature cells would exhibit enhanced contractile performance and the ability to release calcium from the sarcoplasmic reticulum in synchrony, thus enabling the myocardium to function as a syncytium [ 12 ].…”