Pluripotent-cell-derived cardiomyocytes have great potential for use in research and medicine, but limitations in their maturity currently constrain their usefulness. Here, we report a method for improving features of maturation in murine and human embryonic-stem-cell-derived cardiomyocytes (m/hESC-CMs). We found that coculturing m/hESC-CMs with endothelial cells improves their maturity and upregulates several microRNAs. Delivering four of these microRNAs, miR-125b-5p, miR-199a-5p, miR-221, and miR-222 (miR-combo), to m/hESC-CMs resulted in improved sarcomere alignment and calcium handling, a more negative resting membrane potential, and increased expression of cardiomyocyte maturation markers. Although this could not fully phenocopy all adult cardiomyocyte characteristics, these effects persisted for two months following delivery of miR-combo. A luciferase assay demonstrated that all four miRNAs target ErbB4, and siRNA knockdown of ErbB4 partially recapitulated the effects of miR-combo. In summary, a combination of miRNAs induced via endothelial coculture improved ESC-CM maturity, in part through suppression of ErbB4 signaling. Lee et al. report that coculture of embryonic stem cell (ESC)-derived cardiomyocytes with endothelial cells enhances ESC-CM maturity and upregulates several microRNAs. Delivery of selected microRNAs phenocopies this effect, allowing for improved in vitro maturation of ESC-derived cardiomyocytes.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Lee, D. S., Chen, J. H., Lundy, D. J., Liu, C. H., Hwang, S. M., Pabon, L., Shieh, R. C., Chen, C. C., Wu, S. N., Yan, Y. T., Lee, S. T., Chiang, P. M., Chien, S., Murry, C. E., & Hsieh, P. C. H. (2015). Defined MicroRNAs Induce Aspects of Maturation in Mouse and Human Embryonic-Stem-Cell-Derived Cardiomyocytes. Cell Reports, 12(12), 1960-1967. https://doi.org/10.1016/j.celrep.2015.08.042