Cell Stem Cell
Volume 21, Issue 2, 3 August 2017, Pages 179-194.e4
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Article
Human Pluripotent Stem Cell-Derived Atrial and Ventricular Cardiomyocytes Develop from Distinct Mesoderm Populations

https://doi.org/10.1016/j.stem.2017.07.003Get rights and content
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Highlights

  • Human atrial and ventricular cardiomyocytes derive from distinct mesoderm populations

  • Atrial and ventricular mesoderm are distinguished by RALDH2 and CD235a expression

  • Atrial cardiomyocytes are specified by autocrine RA signaling

  • Efficient atrial/ventricular myocyte generation depends on mesoderm patterning

Summary

The ability to direct the differentiation of human pluripotent stem cells (hPSCs) to the different cardiomyocyte subtypes is a prerequisite for modeling specific forms of cardiovascular disease in vitro and for developing novel therapies to treat them. Here we have investigated the development of the human atrial and ventricular lineages from hPSCs, and we show that retinoic acid signaling at the mesoderm stage of development is required for atrial specification. Analyses of early developmental stages revealed that ventricular and atrial cardiomyocytes derive from different mesoderm populations that can be distinguished based on CD235a and RALDH2 expression, respectively. Molecular and electrophysiological characterization of the derivative cardiomyocytes revealed that optimal specification of ventricular and atrial cells is dependent on induction of the appropriate mesoderm. Together these findings provide new insights into the development of the human atrial and ventricular lineages that enable the generation of highly enriched, functional cardiomyocyte populations for therapeutic applications.

Keywords

atrial
ventricular
mesoderm
PSCs
CD235a
RALDH2
differentiation
specification
cardiovascular

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