Reprogramming of Fibroblasts as an Approach to Reduce Heart Fibrosis

There have been a few papers published in recent days covering efforts to reduce fibrosis in the aging heart, and here is another one. Fibrosis is the excessive creation of scar-like structures that disrupt tissue function, and is a consequence of the dysregulation in regenerative processes that occurs with age. There are no truly effective treatments for fibrosis presently available, but several lines of research are quite promising. Senolytic therapies to clear senescent cells in particular should reduce fibrosis, as the link between senescent cells and fibrosis seems clearly established at this time. The other potential approaches involve various ways to interfere with the mechanisms that generate the scarring of fibrosis, in this case by reprogramming the fibroblasts largely responsible for creating fibrotic structures.

During a heart attack, blood stops flowing into the heart; starved for oxygen, part of the heart muscle dies. The heart muscle does not regenerate; instead it replaces dead tissue with scars made of cells called fibroblasts that do not help the heart pump. The heart weakens; most people who had a severe heart attack will develop heart failure, which remains the leading cause of mortality from heart disease. A team of researchers has shown that administration of a cocktail made of transcription factors Gata4, Mef2c and Tbx5 (GMT) results in less scar tissue, or fibrosis, and up to a 50 percent increase in cardiac function in small animal models of the disease. This result was presumed to be mostly a consequence of the reprograming of heart fibroblasts into cardiomyocyte-like cells. Interestingly, the team noticed that reduced fibrosis and improved cardiac function far exceeded the extent of induced new cardiomyocyte-like cells.

"We and others had described that, in addition to inducing reprograming of fibroblasts into cardiomyocyte-like cells, the GMT cocktail also induced reduction of post-heart attack fibrosis. However, not much attention had been paid to the latter." The research team investigated in more detail how the GMT cocktail activated mechanisms that reduced fibrosis. They found the first evidence that, of the three components in the GMT cocktail, only Gata4 was able to reduce post-heart attack fibrosis and improve cardiac function in a rat model of heart attack. Further exploration of the molecular mechanism mediating this novel effect showed that administering Gata4 to rat fibroblasts in the lab resulted in reduced expression of Snail, the master gene of fibrosis. "Gata4 plays a complex role in heart regeneration: as part of the GMT cocktail, it contributes to the reprograming of fibroblasts into cardiomyocyte-like cells; we know it contributes to heart hypertrophy - the development of an enlarged heart - and now we discovered that it alone can decrease cardiac fibrosis. Others have reported that Gata4 also can suppress liver fibrosis. There is still a lot to be done before we can transfer these discoveries to the bedside, but they are important first steps."



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