Defined MicroRNAs Induce Aspects of Maturation in Mouse and Human Embryonic-Stem-Cell-Derived Cardiomyocytes

Desy S. Lee; Jyh Hong Chen; David J. Lundy; Chung Hung Liu; Shiaw Min Hwang; Lil Pabon; Ru Chi Shieh; Chien Chang Chen; Sheng Nan Wu; Yu Ting Yan; Sho Tone Lee; Po Min Chiang; Shu Chien; Charles E. Murry; Patrick C.H. Hsieh

doi:10.1016/j.celrep.2015.08.042

Defined MicroRNAs Induce Aspects of Maturation in Mouse and Human Embryonic-Stem-Cell-Derived Cardiomyocytes

Desy S. Lee, Jyh Hong Chen, David J. Lundy, Chung Hung Liu, Shiaw Min Hwang, Lil Pabon, Ru Chi Shieh, Chien Chang Chen, Sheng Nan Wu, Yu Ting Yan, Sho Tone Lee, Po Min Chiang, Shu Chien, Charles E. Murry, Patrick C.H. Hsieh

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62 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1960-1967
Number of pages	8
Journal	Cell Reports
Volume	12
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2015.08.042
Publication status	Published - Sept 29 2015
Externally published	Yes

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2015.08.042

Cite this

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

@article{5a53d3d51d824156b9b6000d11c23ca8,

title = "Defined MicroRNAs Induce Aspects of Maturation in Mouse and Human Embryonic-Stem-Cell-Derived Cardiomyocytes",

abstract = "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.",

author = "Lee, {Desy S.} and Chen, {Jyh Hong} and Lundy, {David J.} and Liu, {Chung Hung} and Hwang, {Shiaw Min} and Lil Pabon and Shieh, {Ru Chi} and Chen, {Chien Chang} and Wu, {Sheng Nan} and Yan, {Yu Ting} and Lee, {Sho Tone} and Chiang, {Po Min} and Shu Chien and Murry, {Charles E.} and Hsieh, {Patrick C.H.}",

note = "Funding Information: This work was supported by the National Research Program for Biopharmaceuticals of the Ministry of Science and Technology (MOST; 102-2321-B-001-069, 104-2325-B-001-010, and 102-2314-B-039-032) and the Academia Sinica Translational Medicine Program. The Exiqon miRNA microarray assays were performed by the DNA Microarray Core Laboratory at the Institute of Plant and Microbial Biology, Academia Sinica, Taiwan. The authors thank Mr. James Fugate for providing expert training in human cardiac differentiation methods. ",

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doi = "10.1016/j.celrep.2015.08.042",

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AU - Lee, Desy S.

AU - Chen, Jyh Hong

AU - Lundy, David J.

AU - Liu, Chung Hung

AU - Hwang, Shiaw Min

AU - Pabon, Lil

AU - Shieh, Ru Chi

AU - Chen, Chien Chang

AU - Wu, Sheng Nan

AU - Yan, Yu Ting

AU - Lee, Sho Tone

AU - Chiang, Po Min

AU - Chien, Shu

AU - Murry, Charles E.

AU - Hsieh, Patrick C.H.

N1 - Funding Information: This work was supported by the National Research Program for Biopharmaceuticals of the Ministry of Science and Technology (MOST; 102-2321-B-001-069, 104-2325-B-001-010, and 102-2314-B-039-032) and the Academia Sinica Translational Medicine Program. The Exiqon miRNA microarray assays were performed by the DNA Microarray Core Laboratory at the Institute of Plant and Microbial Biology, Academia Sinica, Taiwan. The authors thank Mr. James Fugate for providing expert training in human cardiac differentiation methods.

PY - 2015/9/29

Y1 - 2015/9/29

N2 - 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.

AB - 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.

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ER -

Defined MicroRNAs Induce Aspects of Maturation in Mouse and Human Embryonic-Stem-Cell-Derived Cardiomyocytes

Abstract

ASJC Scopus subject areas

UN SDGs

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