[Sept. 7, 2023: Mark Derewicz, University of North Carolina Health Care]
Scientists at the UNC School of Medicine have made significant advances in the promising field of cellular reprogramming and organ regeneration. (credit: shutterstock)
According to a study led by Li Qian, PhD, at the UNC School of Medicine, a protein that helps make neurons also works to reprogram scar tissue cells into heart muscle cells, specifically formally in partnership with another protein.
Scientists at the UNC School of Medicine have made significant progress in the promising field of cellular reprogramming and organ regeneration, and the discovery could play a major role in future drugs to heal damaged hearts.
In a study published in the journal Cell Stem Cell, scientists at the University of North Carolina at Chapel Hill discovered a more streamlined and efficient method for reprogramming scar tissue cells (fibroblasts) to become healthy heart muscle cells (cardiomyocytes). of.
Fibroblasts produce the fibrous, tough tissue that contributes to heart failure after a heart attack or due to heart disease. The conversion of fibroblasts to cardiomyocytes is being investigated as a potential future strategy to treat or someday cure this common and fatal condition.
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Intriguingly, the key to the new cardiomyocyte-making technique turned out to be a gene activity-regulating protein called Ascl1, which is thought to be a key protein involved in the conversion of fibroblasts to neurons. Researchers thought that Ascl1 was neuron-specific.
“This is an out-of-the-box discovery, and we expect it will be useful in developing future cardiac therapies and potentially other types of therapeutic cellular reprogramming,” said Li Qian, PhD, senior author of the study. said associate professor in the UNC Department of Pathology. Lab Medicine and associate director of the McAllister Heart Institute at the UNC School of Medicine.
Over the past 15 years, scientists have developed various techniques for making stem cells by reprogramming adult cells, then inducing those stem cells to become any other type of adult cell. Recently, scientists have been looking for ways to do this reprogramming more directly – directly from one mature cell type to another.
Human fibroblasts reprogrammed into cardiomyocyte-like cells. Immunofluorescence shows various molecules: DNA (blue), cardiac troponin T (orange) and α-actinin (green). (Credit: UNC Health)
The hope is that when these methods are maximized as safe, effective and efficient, doctors will be able to use a simple injection into patients to reprogram harmful cells into beneficial cells.
“Reprogramming fibroblasts has long been one of the important goals in this field,” Qian said. “The over-activation of fibroblasts causes a number of major diseases and conditions, such as heart failure, chronic obstructive pulmonary disease, liver disease, kidney disease, and brain damage following stroke.”
Ascl1 and Mef2c induce cardiac reprogramming with high efficiency and maturation. (Credit: UNC Health)
In the new study, Qian’s team, which includes co-first-author Haofei Wang, PhD, a postdoctoral researcher, and MD/PhD student Benjamin Keepers, used three techniques to reprogram mouse fibroblasts into cardiomyocytes, liver cells and neurons. existing technologies used. Their aim was to catalog and compare the changes in gene activity patterns and gene-activity regulating factors of cells during these three different reprogrammings.
Unexpectedly, the researchers found that the reprogramming of fibroblasts into neurons activated a set of cardiomyocyte genes. They soon determined that this activation was due to Ascl1, one of the master-programmer “transcription factor” proteins used to make neurons.
From left: Haofei Wang, PhD, Li Qian, PhD, and Benjamin Keepers, who won the 2021 Arts in Science Prize. (Credit: UNC Health)
Since Ascl1 activated cardiomyocyte genes, the researchers added it to the three-transcription-factor cocktail they were using to make cardiomyocytes to see what would happen. They were surprised to find that this dramatically increased the efficiency of reprogramming – the proportion of successfully reprogrammed cells – by more than tenfold. In fact, they found they could now remove two of the three factors from their original cocktail, retaining only Ascl1 and another transcription factor called Mef2c.
In further experiments they found evidence that Ascl1 on its own activates both neuron and cardiomyocyte genes, but when combined with Mef2c it shifts away from a pro-neuron role. In synergy with Mef2c, Ascl1 switches on a broad set of cardiomyocyte genes.
“ASCL1 and MEF2C work together to exert pro-cardiomyocyte effects that neither factor alone does, creating a potent reprogramming cocktail,” Qian said.
The results suggest that key transcription factors used in direct cellular reprogramming are not necessarily specific to a target cell type.
Perhaps more importantly, they represent another step towards future cell-reprogramming therapies for major disorders. Qian says that he and his team hope to create a two-in-one synthetic protein that would contain effective portions of both Ascl1 and Mef2c, and could be injected into failing hearts to repair them.
“Cross-lineage potential of Ascl1 uncovered by comparing diverse reprogramming regulatomes” was co-authored by Haofei Wang, Benjamin Kipers, Yunzhe Qian, Yifang Xie, Marazano Colon, Jiandong Liu, and Li Qian.
Funding was provided by the American Heart Association and the National Institutes of Health (T32HL069768, F30HL154659, R35HL155656, R01HL139976, R01HL139880).
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