Scientists have identified the reason for the lack of ability to regenerate heart muscle cells

Stem cell researchers at the University of California, Los Angeles have discovered why adult heart muscle cells, called cardiomyocytes, have lost their ability to proliferate, and may explain why the human heart has such limited regeneration capacity.

The research, conducted in cell lines and mice, could lead to the development of methods to reprogram cardiac muscle cells directly in patients' hearts, allowing them to create new muscle and repair damage, said Dr. Robb MacLellan of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Unlike newts and salamanders, the adult human body cannot spontaneously regenerate damaged organs such as the heart. However, recent studies show that mammals have the ability to regenerate the heart for a very short period of time – within the first week of life. Then this ability is lost. But if it was there at one time, perhaps it can be restored?

Published in the peer-reviewed Journal of Cell Biology, Dr. McLellan's research shows that it is possible to reset the cellular clock back to a time when cardiomyocytes had the ability to proliferate and repair heart muscle.

“Salamanders and other lower organisms have the ability to dedifferentiate their cardiomyocytes, or revert them to an earlier, more primitive state, allowing these cells to reenter the cell cycle, creating new heart muscle,” says Dr. McLellan, an associate professor of cardiology and physiology. “In mammals, this potential is lost. If we knew how to restore it, or knew the reason why adult cardiomyocytes don’t proliferate, we could try to find a way to regenerate the heart using Nature’s own methods.”

Cardiomyocytes are derived from progenitor stem cells, or precursor cells, that form the heart through proliferation. Once the heart is formed, the myocytes transform from immature to mature cells, which are no longer capable of reproducing. In newts and salamanders, things are different: their cardiomyocytes can revert to an immature, or primitive, state and, once again acquiring the ability to proliferate, repair damage, and then transform back into mature cells.

According to Dr. McLellan, the reason why human cardiomyocytes are unable to do the same is quite simple: in their more primitive state, cardiomyocytes lose the ability to contract normally, which is vital for the proper functioning of the heart. Since humans are much larger than newts and salamanders, our hearts had to be much more efficient to maintain optimal blood pressure and normal circulation.

“As we evolved, in order to maintain optimal blood pressure and circulation, we had to give up the ability to regenerate heart muscle,” says McLellan. “What we gained was more efficient cardiac muscle cells and a heart. But that was a trade-off.”

Dr. McLellan believes that temporarily inhibiting the expression of proteins that block the cell cycle machinery may be able to force adult cardiomyocytes to return to the cell cycle, i.e., to proliferate. These methods should be reversible, so that the effect of targeting the proteins responsible for proliferation disappears after the damage is repaired. The cardiomyocytes would then revert to mature cells and begin to help the restored heart muscle contract. To knock out the proteins that keep the myocytes in a mature state, Dr. McLellan is already considering using nanoparticles to deliver small interfering RNA to the heart.

In a myocardial infarction, part of the heart is no longer supplied with oxygen, and the cardiomyocytes die, being replaced by scar tissue. It is not difficult to find the damaged area of the heart, and if a method is developed for reprogramming the patient's own myocytes, a system that controls the activity of the desired protein and is capable of returning the myocytes to a primitive state can be introduced into the damaged area. This will allow the dead heart muscle to be replaced with a living one.

"The ability of lower organisms to regenerate and why this does not happen in humans has been discussed for a long time. This is the first article that provides an explanation for why this happens," Professor McLellan comments on his work.

There has been much talk about using human embryonic stem cells (hESCs) or reprogrammed induced pluripotent stem cells (iPSCs) to regenerate the heart. However, it is not known what degree of regeneration can be achieved or how significant the benefits might be.

"In my view, this is a potential mechanism for regenerating heart muscle without using stem cells," says Dr. McLellan. "In this case, each person would become a source of cells for their own regeneration."

[ 1 ], [ 2 ], [ 3 ], [ 4 ]