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Proc Natl Acad Sci U S A. 2015 May 26;112(21):E2785-94. doi: 10.1073/pnas.1424042112. Epub 2015 May 11.

Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes.

Author information

1
Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109; Departments of Biochemistry.
2
Computer Science and Engineering, and.
3
Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109; Departments of Biochemistry, Chemistry, University of Washington, Seattle, WA 98195;
4
LabCorp Genomic Services, Seattle, WA 98109;
5
Department of Mechanical Engineering.
6
Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109; Department of Pathology, Center for Cardiovascular Biology.
7
Department of Mechanical Engineering, Department of Bioengineering, and.
8
Computer Science and Engineering, and Department of Genome Sciences, University of Washington, Seattle, WA 98195; Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and.
9
Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109; Department of Pathology, Center for Cardiovascular Biology, Department of Bioengineering, and Department of Medicine/Cardiology and.
10
Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109; Departments of Biochemistry, Department of Bioengineering, and Department of Genome Sciences, University of Washington, Seattle, WA 98195; Department of Biology, University of Washington, Seattle, WA 98195 hannele@uw.edu.

Abstract

In metazoans, transition from fetal to adult heart is accompanied by a switch in energy metabolism-glycolysis to fatty acid oxidation. The molecular factors regulating this metabolic switch remain largely unexplored. We first demonstrate that the molecular signatures in 1-year (y) matured human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are similar to those seen in in vivo-derived mature cardiac tissues, thus making them an excellent model to study human cardiac maturation. We further show that let-7 is the most highly up-regulated microRNA (miRNA) family during in vitro human cardiac maturation. Gain- and loss-of-function analyses of let-7g in hESC-CMs demonstrate it is both required and sufficient for maturation, but not for early differentiation of CMs. Overexpression of let-7 family members in hESC-CMs enhances cell size, sarcomere length, force of contraction, and respiratory capacity. Interestingly, large-scale expression data, target analysis, and metabolic flux assays suggest this let-7-driven CM maturation could be a result of down-regulation of the phosphoinositide 3 kinase (PI3K)/AKT protein kinase/insulin pathway and an up-regulation of fatty acid metabolism. These results indicate let-7 is an important mediator in augmenting metabolic energetics in maturing CMs. Promoting maturation of hESC-CMs with let-7 overexpression will be highly significant for basic and applied research.

KEYWORDS:

cardiac maturation; hESC-cardiomyocyte; let-7; metabolism; microRNA

PMID:
25964336
PMCID:
PMC4450404
DOI:
10.1073/pnas.1424042112
[Indexed for MEDLINE]
Free PMC Article

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