Healing the heart by returning it to its infancy

27 April 2020

Arlene Weintraub / FiercePharma

Nearly a decade ago, researchers at UT Southwestern Medical Center discovered that when mouse hearts were damaged in the first seven days of life, they would regenerate. They reasoned that if they could find a way to recreate that regenerative ability later in life, it might provide a new way to treat heart damage.

Now, that same team has discovered that a protein called calcineurin plays a key role in blocking the ability of heart muscle to regenerate after the first week of life. The discovery could be used to develop treatments that reverse this process, in essence returning the heart to its developmental stage, they reported in the journal Nature.

The discovery builds on previous work at UT Southwestern that focused on the protein Meis1, a transcription factor that prevents heart cells from dividing. When the researchers deleted the gene in mice that makes that protein, their cardiomyocytes continued to divide after the first week of life. But the effect was transient.

Then the researchers discovered that another protein called Hoxb13 was also key, because it shuttles Meis1 into the cell nucleus. So they deleted the genes for both Meis1 and Hoxb13 in adult mice to see what would happen after a heart attack.

It worked. The ability of the animals’ hearts to pump blood quickly returned to near-normal levels, they said. Even though the mice were adults, their hearts looked much like they would in animals that were still developing.

After a series of further experiments, the UT Southwestern scientists discovered that calcineurin regulates both Hoxb13 and Meis1. Inhibiting calcineurin “prolongs the window of cardiomyocyte proliferation,” they wrote in the study.

The idea of treating heart damage by turning back the clock isn’t new. In fact, several research teams have tried using stem cells to repair damaged heart tissue. But those efforts have been disappointing so far.

Last year, a team from the Cincinnati Children's Hospital Medical Center tracked stem cells injected into the hearts of mice and concluded that it was not the cells themselves, but rather their ability to activate macrophage cells from the immune system that promoted healing. That led the researchers to suggest that efforts to regenerate the heart focus less on stem cells and more on other processes in the body that might promote healing.

The discovery of calcineurin’s role in regulating the regeneration of the heart is notable due to the fact that there are already drugs on the market that target the protein. That’s because calcineurin plays a role in a variety of diseases, including rheumatoid arthritis and diabetes. Testing these drugs, either individually or in combination, and developing new medicines that target calcineurin directly could offer new strategies for repairing hearts damaged by heart attacks, high blood pressure, viruses and more, suggested co-author Hesham Sadek, M.D., Ph.D., a professor of internal medicine, molecular biology and biophysics at UT Southwestern.

"By building up the story of the fundamental mechanisms of heart cell division and what blocks it,” Sadek said in a statement, “we are now significantly closer to being able to harness these pathways to save lives.”

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