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

PNAS
Authors
Kavitha T. Kuppusamya,b, Daniel C. Jonesc, Henrik Sperbera,b,d, Anup Madane, Karin A. Fischera,b, Marita L. Rodriguezf, Lil Pabona,g,h, Wei-Zhong Zhua,g,h, Nathaniel L. Tullocha,g,h, Xiulan Yanga,g,h, Nathan J. Sniadeckif,i, Michael A. Laflammea,g,h, Walter L. Ruzzoc,j,k, Charles E. Murrya,g,h,i,l, and Hannele Ruohola-Bakera,b,i,j,m,1
02-24-2016
12:00pm
PST
Categories
Interconnected RNA Processes
Speaker
Roman Camarda
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.