For the first time, UNC scientists detail crucial differences in two leading methods for generating heart muscle cells, a key strategy for new post-heart attack therapies.

Heart disease continues to be the leading cause of death worldwide, partly due to limited therapeutic options and the heart’s inability to regenerate healthy cells called cardiomyocytes after heart attacks. Scientists at the UNC School of Medicine and elsewhere are exploring ways to reprogram scar tissue cells into healthy heart muscle cells, and now UNC researchers have published the first scientific paper to compare in great detail the two leading reprogramming techniques.

Led by Yang Zhou, PhD, a postdoctoral fellow in the laboratory of Li Qian, PhD, assistant professor of pathology and laboratory medicine at UNC, research published in the journal Cell Reports suggests that one method leads to the creation of cardiomyocytes with genetic signatures that closely mimic those found in healthy adult heart muscle cells. The other reprogramming approach leads to the creation of cardiomyocytes with more embryonic cell signatures.

“The differences in the cardiomyocytes generated using these two methods are striking,” said Qian, who is also a member of the UNC McAllister Heart Institute. “Researchers can choose one or the other method based on the specific type of cardiac disease they are interested in studying, while clinicians could carefully select which method is best, considering the pros and cons of each approach.”

Cardiomyocytes, the cells responsible for the beating of the heart, are essential to repairing the heart after injury. But after injury, such as a heart attack, many of these cells are irreversibly lost; they’ve been turned into scar tissue cells. The replacement of these lost cells with patient-specific cardiomyocytes has gained attention as a potential therapy because existing healthy heart tissue better accepts these cells and because of increased recovery rates. Patient-specific cardiomyocytes also offer unique advantages for drug screens to help doctors identify each patient’s tailored drug type and dosage.

There are presently two widely practiced approaches to generate patient-specific cardiomyocytes.

In the first approach, an adult connective cell called a fibroblast is reprogrammed back into a naïve embryonic stem cell-like state. Once in this naïve state, the cell has the potential to develop into any cell type in the body, but researchers direct it to develop into a cardiomyocyte. These newly created cardiomyocytes are called induced pluripotent stem cell cardiomyocytes (iPSC-CM).

In the second approach called direct cardiac reprogramming, a fibroblast is directly converted into a cardiomyocyte, without having to first be reprogrammed into a naïve embryonic stem cell. These new cardiomyocytes are called induced cardiomyocytes (iCM).

Qian lab’s compared cardiomyocytes generated using these two approaches to cardiac fibroblasts and to true cardiomyocytes. The researchers found that both methods resulted in cells with classic cardiomyocyte molecular features. However, by comparing the unique set of genes activated or not activated in each group of cells, the researchers found that iPSC-CMs more closely resembled embryonic cardiomyocytes, while iCMs more closely resembled adult cardiomyocytes.

“This is crucial knowledge,” Qian said. “When developing research projects or creating new therapies, we need to know these sorts of genetic features to best help patients.”

Researchers also found that iPSC-CMs feature more active genes and a higher number of genes poised to be either activated or repressed (known as “epigenetically hyperdynamic”), a trait more commonly found in potent cells.

Metabolically, iPSC-CMs had a higher expression of glycolytic genes while iCMs had a higher expression of genes involved in fatty acid oxidation, the primary means of