Transcription factors can reprogram scar tissue in the heart, but they tend to do so inefficiently, blunting the impact of what could be an effective treatment for heart failure. To give this potential treatment more force, say scientists at the Gladstone Institutes, give the transcription factors some assistance—additional chemicals. In fact, two chemicals have been identified that brought about an eight-fold improvement in cardiac reprogramming, the transformation of scar tissue into healthy, beating heart muscle.
Details of the scientists’ work appeared November 10 in the journal Circulation, in an article entitled “Chemical Enhancement of In Vitro and In Vivo Direct Cardiac Reprogramming.” The article describes how more than 5500 chemicals were tested to improve the ability of three transcription factors—Gata4, Mef2c, and Tbx5 (collectively called GMT)—to turn heart genes on and other genes off in connective tissue cells, effectively regenerating a damaged heart with its own cells.
“We found that a combination of the transforming growth factor (TGF)-β inhibitor SB431542 and the WNT inhibitor XAV939 increased reprogramming efficiency eight-fold when added to GMT-overexpressing cardiac fibroblasts,” wrote the authors of the study. “The small-molecules also enhanced the speed and the quality of cell conversion, as we observed beating cells as early as 1 week after reprogramming compared to 6–8 weeks with GMT alone.”
These results are encouraging because they could help to overcome the shortcomings of the current GMT approach, which typically achieves just a 10% conversion of cells from scar tissue to muscle.
“While our original process for direct cardiac reprogramming with GMT has been promising, it could be more efficient,” said the study’s senior author Deepak Srivastava, M.D., director of the Gladstone Institute of Cardiovascular Disease. “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.
“In vivo, mice exposed to GMT, SB431542, and XAV939 for 2 weeks after myocardial infarction showed significantly improved reprogramming and cardiac function compared to those exposed to only GMT,” the authors continued. “Human cardiac reprogramming was similarly enhanced upon TGF-β and WNT inhibition and was achieved most efficiently with GMT plus Myocardin.”
The scientists noted that the reprogramming of cardiac cells in humans is more complicated that it is in mice. It requires additional factors. Still, the researchers are encouraged that the chemicals they identified will bring them a step closer to better treatments for heart failure, which afflicts 5.7 million Americans, costs the country $30.7 billion every year, and has no cures.
“Heart failure afflicts many people worldwide, and we still do not have an effective treatment for patients suffering from this disease,” said Tamer Mohamed, Ph.D., first author on the study and a former postdoctoral scholar at Gladstone. “With our enhanced method of direct cardiac reprogramming, we hope to combine gene therapy with drugs to create better treatments for patients suffering from this devastating disease.”
