Medical

Flipping the switch on cell conversion could better repair damaged hearts

Flipping the switch on cell conversion could better repair damaged hearts
In the heart of a mouse, a percentage of fibroblast cells, seen in red, have shown markers of endothelial cells, seen in green, following a heart injury
In the heart of a mouse, a percentage of fibroblast cells, seen in red, have shown markers of endothelial cells, seen in green, following a heart injury
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In the heart of a mouse, a percentage of fibroblast cells, seen in red, have shown markers of endothelial cells, seen in green, following a heart injury
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In the heart of a mouse, a percentage of fibroblast cells, seen in red, have shown markers of endothelial cells, seen in green, following a heart injury

One complication that can arise from a heart attack is the formation of scar tissue, which can harden the organ's walls and impede its ability to pump blood. This is caused by fibroblast cells, which move to replace damaged muscle with the scar tissue. New research conducted at the University of North Carolina's (UNC) School of Medicine suggests these cells could be converted to endothelial cells, which actually assist in recovery, potentially minimizing the damage resulting from a heart attack.

While fibroblasts are detrimental to recovery after a heart injury, the endothelial cells create new blood vessels which improve circulation around the damaged area. The balance is sometimes tipped in the damaging cells' favor, however, when the endothelial cells convert into fibrobalsts instead, which compounds the scarring. What the research team at UNC sought to investigate was whether or not this process could work in reverse, turning fibroblasts into endothelial cells and aiding in recovery.

They began by inducing heart attacks in mice and monitoring the fibroblasts for markers that are typically found in the endothelial cells. What they observed was almost a third of the fibroblasts in the injured area expressed markers of endothelial cells, and that they also gave rise to functioning blood vessels.

But to be able to manipulate this process, the researchers needed to identify the molecule that triggered it. They arrived at the protein p53, which is known to cause damaged cells to commit suicide in a process called apoptosis, which can help prevent them from developing into tumors.

With p53 is sparked into action during a heat attack, the team found that it was "overexpressed" in the fibroblast cells, preventing them from switching to endothelial cells. They suspected that if it was the p53 protein that was initially triggering the switch of fibroblasts to endothelial cells, then blocking it should hinder the process. This assumption turned out to be correct, with the researchers observing a 50 percent decrease in cells making the switch once the p53 protein was removed from the equation.

Conversely, the researchers deduced that upping the p53 levels should boost the number of switching cells. And luckily, they had a means to do so. Because p53 becomes mutated or completely absent in cancer cells, there have been a number of drugs developed to increase its levels as an anti-cancer treatment. The team enlisted the help of an experimental drug called Reactivation of p53 and Induction of Tumor cell Apoptosis (RITA), using it to treat mice a few days after heart injury.

The team describes the results as "dramatic," with the number of fibroblasts making the switch to endothelial cells doubling, from 30 percent up to 60 percent.

"The treated mice benefited tremendously," says Eric Ubil, postdoctoral fellow at UNC and author of the study. "There was such a huge decrease in scar formation. We checked the mice periodically, from three days to fourteen days after treatment. They had more blood vessels at the site of injury, and their heart function was better. By increasing the number of blood vessels in the injury region, we were able to greatly reduce the effects of the heart attack."

We have seen fibroblasts championed as an agent for change in treating damaged heart tissue before. Back in 2010, researchers developed a technique to convert fibroblasts into cardiomyocytes, or beating heart cells, potentially giving doctors the ability to better repair tissue following a heart trauma.

The UNC researchers say that treatments based on their findings will still be years away, though the results have given them hope of one day developing more effective treatments. They are currently investigating whether the approach could be applicable to preventing scarring of other organs after injury.

The research findings were published in the journal Nature.

Source: University of North Carolina

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