The protein–protein relationship that could mend a broken heart

Ascl1, a gene activity-controlling protein recognized to be a vital protein involved in the conversion of fibroblasts to neurons, has been found to be the key to a novel cardiomyocyte-creating technology. Ascl1 was previously assumed to be neuron-specific by researchers. Researchers at the University of North Carolina School of Medicine (USA) have made tremendous progress in the promising field of cellular reprogramming and organ regeneration, and the discovery may have a significant impact on future treatments for damaged hearts.

In a study published in the journal Cell Stem Cell, researchers at the University of North Carolina (UNC) at Chapel Hill have developed a faster and more efficient approach for converting scar tissue cells (fibroblasts) into healthy cardiac muscle cells (cardiomyocytes). Fibroblasts are responsible for the fibrous, stiff tissue that leads to heart failure following either a heart attack or heart disease. Transforming fibroblasts into cardiomyocytes is currently being studied as a promising avenue for the treatment or possibly a cure for this prevalent and fatal condition.

Remarkably, the secret to the novel cardiomyocyte-creating process turned out to be Ascl1, a gene activity-controlling protein known to be an important protein in the conversion of fibroblasts to neurons. Ascl1 was previously 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,” comments the 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 UNC School of Medicine.

Over the last 15 years, scientists have devised multiple strategies for reprograming adult cells to become stem cells, then stimulating those stem cells to transform into adult cells of a different type. Scientists have now discovered a technique to perform this reprogramming more immediately, from one mature cell type to another. The aim has been that if these procedures are made as safe, effective, and efficient as possible, clinicians would be able to employ a simple injection into patients to convert 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 this novel study, Qian’s team reprogrammed mice fibroblasts into cardiomyocytes, liver cells, and neurons using three known techniques. Their goal was to document and compare changes in gene activity patterns and gene-activity regulatory factors in cells across these three different approaches.

Surprisingly, the researchers discovered that converting fibroblasts into neurons triggered a group of cardiomyocyte genes. It was quickly realized that this activation was caused by Ascl1, one of the master-programmer “transcription factor” proteins required to create neurons.

Because Ascl1 activated cardiomyocyte genes, the researchers decided to add it to the three-transcription-factor combination they were employing to produce cardiomyocytes to examine the effects. The scientists were shocked to see a more than ten-fold increase in the effectiveness of reprogramming (the fraction of successfully reprogrammed cells). Additionally, it was elucidated that they could now exclude two of the three components from their original combination, keeping simply Ascl1 and another transcription factor known as Mef2c.

Further research revealed that Ascl1 activates both neuron and cardiomyocyte genes on its own but shifts away from the pro-neuron function when Mef2c is present. Ascl1 activates a wide range of cardiomyocyte genes in collaboration with Mef2c.

“Ascl1 and Mef2c work together to exert pro-cardiomyocyte effects that neither factor alone exerts, making for a potent reprogramming cocktail,” Qian stated.

These findings indicate that the primary transcription factors employed in direct cellular reprogramming are not necessarily restricted to a single cell type. Perhaps even more crucially, these findings are another step forward in the development of future cell-reprogramming medicines for major diseases. Qian and her colleagues seek to develop a two-in-one synthetic protein that comprises the active portions of both Ascl1 and Mef2c, which may be injected into failing hearts to repair them.

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