Re-engineering the heart with the correct components

Modulation of retinoic acid signaling generates atrial versus ventricular cardiomyocytes from human induced pluripotent stem cells. Human pluripotent stem cells have emerged as a valuable tool to study human cardiomyocyte biology and genetic cardiomyopathies, and they represent a promising approach to generate cardiomyocytes for regenerative medicine applications. Unfortunately, many of the directed differentiation protocols currently used to produce cardiomyocytes from either human embryonic stem cells or induced pluripotent progenitors yield mixed cultures of atrial cardiomyocytes, ventricular cardiomyocytes, and cardiac conduction cells. The inability to generate pure cardiac cell populations is an obstacle that needs to be overcome to realize the full diagnostic and therapeutic potential of human pluripotent stem cell-derived cardiomyocyte systems. Cyganek et al. applied a simplied and robust method to direct the selective differentiation of atrial and ventricular cardiomyocytes from human induced pluripotent stem cells (hiPSCs). Using three independent human pluripotent stem cell lines and stage-specic modulation of retinoic acid and WNT signaling, the authors performed detailed morphologic, transcriptomic, proteomic, and electrophysiologic phenotyping of atrial and ventricular hiPSC-derived cardiomyocytes. Through these analyses they showed critical distinctions between cell types that are consistent with previously dened characteristics of human atrial and ventricular cardiomyocytes. Using engineered heart tissues, they also demonstrated important mechanical differences between tissues derived from atrial versus ventricular cardiomyocytes, such as force and dynamics of contraction, calcium and carbachol sensitivity, and spontaneous contraction. Collectively, these ndings are transformative and highlight the need to continue to rene protocols for the generation of cardiomyocytes from human progenitor cells. Production of appropriate cardiac cell types will be essential for the success of in vitro systems to dene mechanisms of genetic cardiomyopathies, screen for therapeutics, and develop cell types and tissues for regenerative medicine applications. Future studies will need to focus on methods to specify specic heart chambers (left versus right ventricle) and accelerate cardiomyocyte maturation.