A multi-university team of researchers has identified a molecular switch that seems to be essential for embryonic heart cells to grow into more mature, adult-like heart cells. The discovery should help scientists better understand how human hearts mature.
The group believes its finding will be of particular interest to stem cell and regenerative medicine researchers as it may lead to laboratory methods to create heart cells that function more like those found in adult hearts. The molecular switch is described in a paper (“Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes”) in the Proceedings of the National Academy of Sciences.
“Although we can now induce embryonic stem cells to become heart cells, getting them to mature to an adult-like state remains a significant challenge,” said Hannele Ruohola-Baker, Ph.D., University of Washington professor of biochemistry and senior author of the paper. “We believe we've now found the master switch that drives the maturation process.”
In the months before and after birth, an infant's heart cells undergo dramatic changes. The cells enlarge, develop complex elements that enable them to contract, and switch from a metabolism that depends on glucose for most of its energy to a metabolism that derives most of its energy from fats. As a result of these changes, the newborn's heart grows bigger, stronger, and far more energy efficient. Relatively little is known about how this maturation takes place.
In the new study, Kavitha T. Kuppusamy, Ph.D., the lead author in the article and senior fellow in Dr. Ruohola-Baker's lab, performed transcriptome analysis of RNA produced in 20-day-old human embryonic stem cell-derived cardiomyocytes and in more mature, 13-month-old versions of these cells. This type of analysis details the types and levels of RNA produced in cells at a particular time.
Drs. Kuppusamy and Ruohola-Baker were especially interested in microRNA, which plays a key role in controlling gene expression and, thereby, helps regulate the cell's development, growth, and function.
“When we compared microRNA levels seen in the 20-day-old cardiomyocytes and the more mature 13-month-old cardiomyocytes, one microRNA family, called let-7, stood out,” noted Dr. Kuppusamy. “Other miRNAs were being expressed in high levels in the more mature cells, but let-7 had increased 1000-fold. Interestingly, the let-7 family of micro RNA affects several key genes that regulate glucose metabolism, called the PI3/AKT/insulin pathway.”
To further explore the role let-7 microRNA in cardiac cell maturation, Dr. Kuppusamy and her colleagues looked to the effects increasing and lowering let-7 levels had on the hECS-CMs [human embryonic stem cells-cardiomyocytes]. They found that when they decreased let-7 levels, the cells reverted to a glucose-based metabolism and became smaller, weaker, and structurally and functionally less mature. On the other hand, when they increased let-7 levels, the cells switched to a fatty acid-based metabolism and became larger, stronger, and structurally and functionally more mature.
In addition to its effect on the insulin pathway, the let-7 microRNA appears to drive these metabolic and functional changes by acting on other key gene regulators. Among these is the enzyme EZH2 that affects the expression of a wide variety of genes, including those involved in cell development and differentiation.
“These results indicate let-7 is an important mediator in augmenting metabolic energetics in maturing CMs,” wrote the investigators. “Promoting maturation of hESC-CMs with let-7 overexpression will be highly significant for basic and applied research.”