A recent study has discovered a quicker and more efficient method to rewire scar tissue cells (fibroblasts) into sound heart muscle cells.
The UNC School of Medicine’s researchers have achieved significant advances in the fascinating fields of cellular reprogramming and organ regeneration, and their discoveries may have a significant influence on the creation of future therapies for shattered hearts.
In a study that was published in the journal Cell Stem Cell, researchers at the University of North Carolina in Chapel Hill discovered a more efficient method for reprogramming scar tissue cells (fibroblasts) to develop into healthy cardiac muscle cells (cardiomyocytes). Fibroblasts produce the fibrous, stiff tissue that leads to heart failure following a heart attack or as a result of cardiac illness. By transforming fibroblasts into cardiomyocytes, researchers hope to treat or eventually cure this devastating and prevalent disease.
Unexpectedly, the novel method for producing cardiomyocytes was based on a gene activity-controlling protein called Ascl1, which is known to be crucial for transforming fibroblasts into neurons. Researchers initially believed that Ascl1 was neuron-specific.
“It’s an out-of-the-box finding, and we expect it to be valuable in designing future cardiac therapies and maybe other types of therapeutic cellular reprogramming,” said Li Qian, PhD, senior author of the study and associate director of the McAllister Heart Institute at the UNC School of Medicine.
Researchers have developed a number of techniques over the past 15 years to transform adult cells into stem cells and then stimulate those stem cells to differentiate into different kinds of adult cells. In recent years, scientists have developed methods for directly reprogramming cells from one mature cell type to another. It has been believed that once these procedures are as secure, reliable, and effective as feasible, doctors will be able to directly inject patients with dangerous cells-turned-beneficial 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 reprogramme 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 researchers found that fibroblast to neuron conversion triggered a set of genes associated with cardiomyocytes. They rapidly realised that this activation was being caused by Ascl1, one of the master-programmer “transcription factor” proteins used to construct the neurons.
Ascl1 triggered the genes for cardiomyocytes, so the researchers added it to the three transcription factor combinations they had been using to make cardiomyocytes to see what would happen. They were astounded to discover that it had a ten-fold boost in reprogramming efficiency, or the proportion of successfully reprogrammed cells. In fact, they found that of their initial trio of three transcription factors, only Ascl1 and another transcription factor known as Mef2c were still present.