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iPSCs and Advanced Screening Support Drug Discovery for Atrial Fibrillation

Review of "Drug Screening Platform Using Human Induced Pluripotent Stem Cell-Derived Atrial Cardiomyocytes and Optical Mapping" from STEM CELLS Translational Medicine by Stuart P. Atkinson

The differentiation of human induced pluripotent stem cells (iPSCs) into cardiomyocytes has provided a tractable in vitro model system that allows the precise study of cardiac disease physiology and pharmacology. In the hope of discovering treatment options for atrial fibrillation, the most common heart rhythm disorder, a range of studies has explored the differential pharmacology of stem cell‐derived atrial cardiomyocytes employing a limited number of test compounds and low throughput measurement systems [1-3].

To boost the translational potential of this strategy, researchers led by Glen F. Tibbits (British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada) recently developed an advanced in vitro drug screening platform that employed high‐content optical mapping to simultaneously measure membrane potential and Ca2+ transients at a high‐resolution in iPSC‐derived atrial cardiomyocytes [4]. Their exciting results, reported recently in STEM CELLS Translational Medicine [5], may significantly accelerate the identification of novel drugs for the treatment of atrial fibrillation.

Gunawan et al. began by precisely modulating both the WNT and retinoic acid signaling pathways, an approach based on a well-characterized cardiomyocyte differentiation protocol using small molecular inhibitors [4], to foster the highly efficient differentiation of iPSCs into a homogeneous population of atrial cardiomyocytes. While transcriptomic and proteomic analyses validated the human atrial phenotype of the generated cells, the team also employed their optical mapping methodology for functional characterization (in parallel with conventional established functional assays) to establish that iPSC-derived atrial cardiomyocytes displayed shorter action potential durations and more rapid Ca2+ handling dynamics when compared to iPSC-derived ventricular cardiomyocytes. Overall, the authors provide evidence that their iPSC-derived atrial cardiomyocytes display the molecular and functional characteristics of native atrial tissue and, therefore, represent an exciting new means to study atrial physiology.

Subsequent exploration of existing clinical and experimental drugs with atrial‐selective effects using optical mapping in iPSC-derived atrial cardiomyocytes highlighted greater sensitivity for 4‐aminopyridine, AVE0118, UCL1684, and also vernakalant, a clinically approved atrial‐selective compound for the intravenous cardioversion of atrial fibrillation when compared to a similar analysis in iPSC-derived ventricular cardiomyocytes. These findings suggest the applicability of this preclinical human‐relevant in vitro screening strategy to identify novel atrial-selective drugs for the treatment of atrial fibrillation.

The authors highlight the immature state of the generated cardiomyocytes as the main limitation of their study [6]; however, the obvious nature of the differences between the atrial and ventricular cardiomyocytes lends credence to their highly encouraging findings.

For more on the generation of atrial and ventricular cardiomyocytes from pluripotent stem cells and the search for atrial-specific drugs, stay tuned to the Stem Cells Portal.

Results

  1. Laksman Z, Wauchop M, Lin E, et al., Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue. Scientific Reports 2017;7:5268.
  2. Argenziano M, Lambers E, Hong L, et al., Electrophysiologic Characterization of Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Atrial Cardiomyocytes. Stem Cell Reports 2018;10:1867-1878.
  3. Cyganek L, Tiburcy M, Sekeres K, et al., Deep phenotyping of human induced pluripotent stem cell–derived atrial and ventricular cardiomyocytes. JCI Insight 2018;3.
  4. Lian X, Zhang J, Azarin SM, et al., Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions. Nature Protocols 2013;8:162-175.
  5. Gunawan MG, Sangha SS, Shafaattalab S, et al., Drug screening platform using human induced pluripotent stem cell-derived atrial cardiomyocytes and optical mapping. STEM CELLS Translational Medicine 2021;10:68-82.
  6. Tu C, Chao Benjamin S, and Wu Joseph C, Strategies for Improving the Maturity of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Circulation Research 2018;123:512-514.