Atrial fibrillation is believed to afflict approximately six million people in Europe, rendering it the most common arrhythmia dealt with in clinics.
The irregular heartbeat and disturbed electrical activity which affect atrial fibrillation patients are typically treated via surgical interventions, including pacemakers or the ablation of diseased tissue, or using non-selective class IC (Nav) and III (Kv) ion channel anti-arrhythmic drugs.
Unfortunately, these strategies can be accompanied by severe side-effects. Therefore, substantial research has been undertaken to improve the understanding of the cellular mechanisms underpinning the disease, in order to develop safer and more effectual therapies.
However, drug discovery attempts facilitated by conventional preclinical animal and non-cardiac cell
models of atrial fibrillation have attained limited success in realizing this objective. One crucial limiting factor is that such systems are often unable to reliably simulate the physiology of human atrial cardiomyocytes.
Alternative models which employ human atrial cardiomyocyte primary cells embody greater potential. Nevertheless, the viability and yield of live cells from human hearts is low, and research can only be undertaken utilizing restricted amounts of material. Moreover, native human tissue normally derives from diseased donors and is typically very fibrous, thus making it hard to work with.
Human induced pluripotent stem cell (iPSC)-derived atrial cardiomyocytes can represent a better alternative. They provide a robust model system for atrial fibrillation drug discovery and disease modeling due to three important advantages:
- They supply insights with increased translational relevance
- They provide greater consistency
- They are easier to use from a practical perspective
This paper will investigate how each of these benefits is helping to accelerate the delivery of progressive anti-arrhythmic drugs to patients.
iPSC-derived Atrial Cardiomyocytes Provide More Physiologically Relevant Insight
In numerous areas of human disease modeling and drug discovery, the translation of findings and predictions from test systems to patients urgently needs improving. iPSC-derived cells can be helpful in solving this problem, as they can be utilized in the creation of models that more accurately reflect native human cells and tissues, in comparison to in vitro and animal in vivo systems. This helps to minimize the opportunity for unanticipated side-effects while also reducing rates of attrition.
In this manner, human iPSC-derived atrial cardiomyocytes represent a perfect platform for modeling atrial fibrillation, as they manifest all of the physiological properties of native human atrial cells. Axol’s researchers have developed a line of iPSC-derived atrial cardiomyocytes that can be utilized as a robust platform for supporting drug discovery in this sector. The cells were generated from iPSCs using footprint-free episomal reprogramming methodologies, and via the integration of specific differentiation factors at critical time points to drive atrial fate.
Such iPSC-derived atrial cardiomyocytes embody important genotypic and phenotypic properties, which render them a translationally advantageous in vitro system for reliable atrial fibrillation disease modeling and ion channel target drug discovery. Biophysical and pharmacological characterization research into these cells has indicated that they manifest a broad range of functional features associated with healthy atrial cardiomyocytes, such as physiologically relevant action potential parameters (Figure 1).
Figure 1: Atrial-specific ion channel pharmacology of iPSC-derived cardiomyocytes. Manual patch current clamp recordings of spontaneous action potentials (APs) reveal characteristic effects of selective modulators of (A) Ikur (50 μM 4-AP) and (B) IKACh channels (1 μM carbachol) known to be selectively expressed in human atria. Data generated in collaboration with Metrion Biosciences.
iPSC-derived Atrial Cardiomyocytes Deliver More Consistent Results
For atrial cardiomyocytes to be effective as translationally predictive and reliable models within disease research, reproducibility and consistency are crucial. One of the largest challenges related to the utilization of native human cardiomyocytes is that the consequent data can vary substantially.
Such variability is caused by intra- and inter-patient divergences, in addition to the impact of harsh isolation techniques on delicate cells and tissues. As a result, larger samples are needed in order to demonstrate significant treatment effects.
Alternatively, more consistent data can be acquired from in vitro iPSC-derived atrial cardiomyocyte assays, lowering expenses and data delivery timescales, while also enhancing data quality and predictive power. Axol’s iPSC-derived atrial cardiomyocytes are produced from a young, healthy donor, which is not always the case when native human atrial cells are taken from atrial fibrillation patients (who are typically older and present with fibrous atrial appendages). A number of these patients are affected by chronic disease and have undertaken multiple drug therapies, further augmenting the variability of their baseline data before compound screening.
The biophysical and pharmacological profiles of these human iPSC-derived atrial cardiomyocytes were also shown to be extremely consistent between pilot batches and commercial scale-up materials, thus reducing variability even more. As batch-to-batch reproducibility is critical when utilizing cell reagents and assays for drug discovery screening and disease modeling, such a high level of consistency renders them a reliable source of cells for both.
iPSC-derived Atrial Cardiomyocytes are Easier to Handle
Utilizing native human atrial cardiomyocytes for disease modeling and drug discovery efforts can pose challenges as a result of the complexities related to sourcing, extracting and culturing primary cell lines. In comparison, human iPSC-derived atrial cardiomyocytes provide much better convenience and ease of use.
One of the greatest benefits supplied by human iPSC-derived models is the ease with which the sourcing of cells occurs – either by the quick delivery of fresh cells or via the storage of frozen cells. This ready supply of reliable and consistent human iPSC-derived atrial cardiomyocytes enables researchers to utilize larger amounts of material from the same differentiation batch, thus boosting the statistical importance of experimental findings.
The ease of sourcing iPSC-derived cells can also assist in facilitating augmented planning and execution of experiments; for example, quickening the delivery of screening data against tight timelines. The robust phenotype of Axol’s human iPSC-derived atrial cardiomyocytes offers support to the complex experiments required for aligning iPSC data with native tissue data, in addition to more conventional screening experiments that are undertaken utilizing industry-standard, plate-based assay platforms.
A Robust Platform For Disease Modelling and Drug Discovery
iPSC-derived atrial cardiomyocytes represent an extremely consistent and translationally useful platform for disease modeling, capable of supporting a broad array of drug discovery applications. By overcoming a number of the limitations related to conventional native human cell lines and non-human animal models, iPSC-derived atrial cardiomyocytes are about to open up a world of opportunity for atrial fibrillation researchers. Download the white paper (developed in conjunction with Metrion Biosciences) to find out more about how Axol’s validated iPSC-derived atrial cardiomyocytes could enhance a research program.
About AXOL Biosciences
Axol specializes in human cell culture.
Axol produces high quality human cell products and critical reagents such as media and growth supplements. We have a passion for great science, delivering epic support and innovating future products to help our customers advance faster in their research.
Our expertise includes reprogramming cells to iPSCs and then differentiating to various cell types. We supply differentiated cells derived from healthy donors and patients of specific disease backgrounds. As a service, we also take cells provided by customers (primary or iPSC) and then do the reprogramming (when necessary) and differentiation. Clearly, by offloading the burden of generating cells, your time is freed up to focus on the research. Axol holds the necessary licenses that are required to do iPSC work.
The package wouldn't be complete without optimized media, coating solutions and other reagents. Our in-house R&D team works hard to improve on existing media and reagents as well as innovate new products for human cell culture. We also supply a growing range of human primary cells; making Axol your first port of call for your human cell culture needs.
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