Researchers at the UNC School of Medicine have made important strides in the exciting fields of cellular reprogramming and organ regeneration, and their findings could have a substantial impact on the development of future treatments for damaged hearts.
Researchers from the University of North Carolina at Chapel Hill found a more streamlined and effective way to transform scar tissue cells (fibroblasts) into healthy heart muscle cells (cardiomyocytes) in a study that was published in the journal Cell Stem Cell.
The fibrous, stiff tissue that causes heart failure after a heart attack or because of cardiac disease is created by fibroblasts. Researchers are looking into the possibility of treating or maybe one day curing this widespread and deadly illness by converting fibroblasts into cardiomyocytes.
Surprisingly, a gene activity-controlling protein called Ascl1, which is well recognized to be an essential protein involved in converting fibroblasts into neurons, turned out to be the key to the new cardiomyocyte-making approach. Ascl1 was once assumed to be neuron-specific by researchers.
“It’s an outside-the-box finding, and we expect it to be useful in developing future cardiac therapies and potentially other kinds of therapeutic cellular reprogramming,” said study senior author Li Qian, PhD, associate professor in the UNC Department of Pathology and Lab Medicine and associate director of the McAllister Heart Institute at the UNC School of Medicine.
In the past 15 years, researchers have created several methods to convert adult cells into stem cells and then drive those stem cells to differentiate into other types of adult cells. Recently, researchers have discovered strategies to reprogram cells directly from one mature cell type to another.
It has been hoped that once these techniques are as safe, effective, and efficient as possible, clinicians will provide a straightforward injection to patients to transform harmful cells into helpful ones.
“Reprogramming fibroblasts has long been one of the important goals in the field,” Qian said. “Fibroblast over-activity underlies many major diseases and conditions including heart failure, chronic obstructive pulmonary disease, liver disease, kidney disease, and the scar-like brain damage that occurs after strokes.”
In the new study, Qian's team used three currently used approaches to reprogram mice fibroblasts into cardiomyocytes, liver cells, and neurons. This team also included co-first authors Haofei Wang, PhD, a postdoctoral researcher, and MD/PhD student Benjamin Keepers. Their goal was to document and contrast the variations in gene activity patterns and variables that control gene activity during these three separate reprogrammings.
Unexpectedly, the scientists discovered that converting fibroblasts into neurons activated a group of genes related to cardiomyocytes. They quickly discovered that Ascl1, one of the master-programmer "transcription factor" proteins that had been employed to create the neurons, was the cause of this activation.
The researchers added Ascl1 to the three-transcription factor cocktail they had been using to create cardiomyocytes to see what would happen because Ascl1 activated cardiomyocyte genes. They were shocked to see that it significantly increased reprogramming efficiency—the percentage of effectively reprogrammed cells—by over ten times. In reality, they discovered that only Ascl1 and another transcription factor known as Mef2c remained from their original cocktail of three factors.
Further research revealed that Ascl1 activates the genes for both cardiomyocytes and neurons on its own, but that it shifts away from the pro-neuron position in the presence of Mef2c. Ascl1 activates a wide range of genes related to cardiomyocytes in cooperation with Mef2c.
“Ascl1 and Mef2c work together to exert pro-cardiomyocyte effects that neither factor alone exerts, making for a potent reprogramming cocktail,” Qian said.
The findings show that the key transcription factors involved in direct cellular reprogramming are not always exclusive to the cell type being altered.
More importantly, they represent a development toward potential cell-reprogramming treatments for serious diseases. To repair failing hearts, Qian and her team plan to create a two-in-one synthetic protein that combines the active components of Ascl1 and Mef2c.