Scientists have discovered a protein that restores the heart muscle and regenerates organs

Scientists at the University of North Carolina School of Medicine have made significant progress in the promising field of cellular reprogramming and organ regeneration. (CREDIT: Shutterstock)

The protein that helps build neurons also works to reprogram scar tissue cells into heart muscle cells, especially in partnership with a second protein, according to a study by Li Qian, Ph.D., at the University of North Carolina School of Medicine.

Scientists at the University of North Carolina School of Medicine have made significant progress in the promising field of cellular reprogramming and organ regeneration, and this discovery could play an important role in future drugs to treat damaged hearts.

In a study published in the journal Cell Stem Cell, scientists at the University of North Carolina at Chapel Hill have found a smarter and more efficient way to reprogram scar tissue cells (fibroblasts) into healthy heart muscle cells (cardiomyocytes).

Fibroblasts produce fibrous, tough tissue that contributes to heart failure after a heart attack or due to heart disease. The transformation of fibroblasts into cardiomyocytes is being studied as a potential future strategy for treating or even curing this common and deadly disease.

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Surprisingly, the key to the new technique for creating cardiomyocytes turned out to be the Ascl1 protein, which controls the activity of the gene, which is known to be a key protein involved in the transformation of fibroblasts into neurons. The researchers thought that Ascl1 was specific to neurons.

“This is an unorthodox finding, and we expect it to be useful in the development of future cardiac therapies and possibly other types of therapeutic cellular reprogramming,” said study senior author Li Qian, Ph.D., assistant professor of pathology and medicine at the University of North Carolina. Laboratory medicine and associate director of the McAllister Heart Institute at the University of North Carolina School of Medicine.

Scientists over the past 15 years have developed various methods to reprogram adult cells into stem cells and then force those stem cells to become a different type of adult cell. More recently, scientists have found ways to make this reprogramming more direct—straight from one mature cell type to another.

Human fibroblasts are reprogrammed into cardiomyocyte-like cells. Immunofluorescence shows different molecules: DNA (blue), cardiac troponin T (orange) and α-actinin (green). (CREDIT: UNC Health)

It was hoped that when these methods became as safe, effective and efficient as possible, doctors could use a simple injection to patients to reprogram harmful cells into useful ones.

“Fibroblast reprogramming has long been one of the important challenges in this field,” Qian said. “Fibroblast overactivity underlies many serious diseases and conditions, including heart failure, chronic obstructive pulmonary disease, liver disease, kidney disease, and brain scarring that occurs after strokes.”

Ascl1 and Mef2c induce heart reprogramming with high efficiency and maturity. (CREDIT: UNC Health)

In the new study, Qian’s team, including co-authors Haofei Wang, PhD, PhD researcher and graduate student Benjamin Keepers, used three existing methods to reprogram mouse fibroblasts into cardiomyocytes, liver cells, and neurons. Their goal was to catalog and compare changes in cell gene activity patterns and gene regulation factors during these three different reprogrammings.

Unexpectedly, the researchers found that reprogramming fibroblasts into neurons activates a set of cardiomyocyte genes. They soon determined that this activation was caused by Ascl1, one of the main “transcription factor” proteins used to make neurons.

From left to right: Haofei Wang, Ph.D., Li Qian, Ph.D., and Benjamin Keepers, winner of the 2021 Art in Science Award. (PREDICTION: UNC Health)

Because Ascl1 activated cardiomyocyte genes, the researchers added it to a cocktail of three transcription factors they used to create cardiomyocytes to see what would happen. They were amazed to find that this significantly increased the efficiency of reprogramming – the proportion of cells successfully reprogrammed – by more than tenfold. In fact, they found that they could now do without two of the three factors from the original cocktail, retaining only Ascl1 and another transcription factor, named Mef2c.

In further experiments, they found evidence that Ascl1 by itself activates genes in both neurons and cardiomyocytes, but deviates from the role of proneurons when accompanied by Mef2c. In synergy with Mef2c, Ascl1 includes a wide range of cardiomyocyte genes.

“Ascl1 and Mef2c work together to exert a procardiomyocyte effect that neither factor does alone, creating a powerful reprogramming cocktail,” Qian said.

The results show that the major transcription factors used in direct cellular reprogramming are not necessarily exclusive to one type of target cell.

Perhaps more importantly, they represent another step towards future methods of reprogramming cells to treat serious diseases. Qian says she and her team hope to create a synthetic two-in-one protein that contains effective fragments of both Ascl1 and Mef2c and can be injected into a diseased heart to cure it.

Co-authored with Haofei Wang, Benjamin Keepers, Yunzhe Qiang, Yifan Xie, Marazzano Colon, Jiangdong Liu, and Li Qiang, wrote “Potential for Ascl1 Interlinear Origin Discovered by Comparing Different Reprogramming Regulators”.

Funding was provided by the American Heart Association and the National Institutes of Health (T32HL069768, F30HL154659, R35HL155656, R01HL139976, R01HL139880).

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Note. Materials provided above by the University of North Carolina Health. Content can be edited for style and length.

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