An Update on Reversing Heart Scarring via Gata4, Mef2c, and Tbx5

Four years ago, researchers reported that they could use gene therapy to increase levels of Gata4, Mef2c, and Tbx5 in order to provoke the conversion of a fraction of scar tissue into healthy muscle tissue in damaged hearts. This seems a promising approach, but like many fields of research it is proceeding only slowly. Here is a recent update, in which the researchers report on efforts to make the conversion process more efficient and thus practical as the basis for a therapy:

Scientists are exploring cellular reprogramming - turning one type of adult cell into another - in the heart as a way to regenerate muscle cells in the hopes of treating, and ultimately curing, heart failure. It takes only three transcription factors - proteins that turn genes on or off in a cell - to reprogram connective tissue cells into heart muscle cells in a mouse. After a heart attack, connective tissue forms scar tissue at the site of the injury, contributing to heart failure. The three factors, Gata4, Mef2c, and Tbx5 (collectively known as GMT), work together to turn heart genes on in these cells and turn other genes off, effectively regenerating a damaged heart with its own cells. But the method is not foolproof - typically, only ten percent of cells fully convert from scar tissue to muscle.

In the new study, scientists tested 5500 chemicals to try to improve this process. They identified two chemicals that increased the number of heart cells created by eightfold. Moreover, the chemicals sped up the process of cell conversion, achieving in one week what used to take six to eight weeks. "While our original process for direct cardiac reprogramming with GMT has been promising, it could be more efficient. With our screen, we discovered that chemically inhibiting two biological pathways active in embryonic formation improves the speed, quantity, and quality of the heart cells produced from our original process."

The first chemical inhibits a growth factor that helps cells grow and divide and is important for repairing tissue after injury. The second chemical inhibits an important pathway that regulates heart development. By combining the two chemicals with GMT, the researchers successfully regenerated heart muscle and greatly improved heart function in mice that had suffered a heart attack. The scientists also used the chemicals to improve direct cardiac reprogramming of human cells, which is a more complicated process that requires additional factors. The two chemicals enabled the researchers to simplify the process bringing them one step closer to better treatments for heart failure.



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