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

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)1960-1967
Number of pages8
JournalCell Reports
Volume12
Issue number12
DOIs
Publication statusPublished - 2015 Sep 29

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Stem cells
MicroRNAs
Cardiac Myocytes
Embryonic Stem Cells
Endothelial cells
Coculture Techniques
Up-Regulation
Endothelial Cells
Bioelectric potentials
Sarcomeres
Human Embryonic Stem Cells
Mouse Embryonic Stem Cells
Luciferases
Small Interfering RNA
Medicine
Assays
Membrane Potentials
Calcium
Membranes
Research

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lee, D. S., Chen, J. H., Lundy, D. J., Liu, C. H., Hwang, S. M., Pabon, L., ... 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
Lee, Desy S. ; Chen, Jyh Hong ; Lundy, David J. ; Liu, Chung Hung ; Hwang, Shiaw Min ; Pabon, Lil ; Shieh, Ru Chi ; Chen, Chien Chang ; Wu, Sheng Nan ; Yan, Yu Ting ; Lee, Sho Tone ; Chiang, Po Min ; Chien, Shu ; Murry, Charles E. ; Hsieh, Patrick C.H. / Defined MicroRNAs Induce Aspects of Maturation in Mouse and Human Embryonic-Stem-Cell-Derived Cardiomyocytes. In: Cell Reports. 2015 ; Vol. 12, No. 12. pp. 1960-1967.
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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.",
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Lee, DS, Chen, JH, Lundy, DJ, Liu, CH, Hwang, SM, Pabon, L, Shieh, RC, Chen, CC, Wu, SN, Yan, YT, Lee, ST, Chiang, PM, Chien, S, Murry, CE & Hsieh, PCH 2015, 'Defined MicroRNAs Induce Aspects of Maturation in Mouse and Human Embryonic-Stem-Cell-Derived Cardiomyocytes', Cell Reports, vol. 12, no. 12, pp. 1960-1967. https://doi.org/10.1016/j.celrep.2015.08.042

Defined MicroRNAs Induce Aspects of Maturation in Mouse and Human Embryonic-Stem-Cell-Derived Cardiomyocytes. / Lee, Desy S.; Chen, Jyh Hong; Lundy, David J.; Liu, Chung Hung; Hwang, Shiaw Min; Pabon, Lil; Shieh, Ru Chi; Chen, Chien Chang; Wu, Sheng Nan; Yan, Yu Ting; Lee, Sho Tone; Chiang, Po Min; Chien, Shu; Murry, Charles E.; Hsieh, Patrick C.H.

In: Cell Reports, Vol. 12, No. 12, 29.09.2015, p. 1960-1967.

Research output: Contribution to journalArticle

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T1 - Defined MicroRNAs Induce Aspects of Maturation in Mouse and Human Embryonic-Stem-Cell-Derived Cardiomyocytes

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.

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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