title: Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes.
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.
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109; Departments of Biochemistry.
authors.forename: Kavitha T
authors.initials: KT
authors.lastname: Kuppusamy
authors.affiliation: Computer Science and Engineering, and.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Jones
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109; Departments of Biochemistry, Chemistry, University of Washington, Seattle, WA 98195;
authors.forename: Henrik
authors.initials: H
authors.lastname: Sperber
authors.affiliation: LabCorp Genomic Services, Seattle, WA 98109;
authors.forename: Anup
authors.initials: A
authors.lastname: Madan
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109; Departments of Biochemistry.
authors.forename: Karin A
authors.initials: KA
authors.lastname: Fischer
authors.affiliation: Department of Mechanical Engineering.
authors.forename: Marita L
authors.initials: ML
authors.lastname: Rodriguez
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109; Department of Pathology, Center for Cardiovascular Biology.
authors.forename: Lil
authors.initials: L
authors.lastname: Pabon
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109; Department of Pathology, Center for Cardiovascular Biology.
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Zhu
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109; Department of Pathology, Center for Cardiovascular Biology.
authors.forename: Nathaniel L
authors.initials: NL
authors.lastname: Tulloch
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109; Department of Pathology, Center for Cardiovascular Biology.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Mechanical Engineering, Department of Bioengineering, and.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Sniadecki
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109; Department of Pathology, Center for Cardiovascular Biology.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laflamme
authors.affiliation: Computer Science and Engineering, and Department of Genome Sciences, University of Washington, Seattle, WA 98195; Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and.
authors.forename: Walter L
authors.identifier: http://orcid.org/0000-0002-6260-2926
authors.initials: WL
authors.lastname: Ruzzo
authors.affiliation: 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.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Murry
authors.affiliation: 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.
authors.forename: Hannele
authors.initials: H
authors.lastname: Ruohola-Baker
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D004734:Energy Metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008955:Models, Cardiovascular; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D023822:Tissue Engineering; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs; C487931:mirnlet7 microRNA, human
keywords: cardiac maturation; hESC-cardiomyocyte; let-7; metabolism; microRNA