Stem cell researchers at University of California, Los Angeles (UCLA) have uncovered for the first time why adult human cardiac myocytes — specialized muscle cells in the heart — have lost their ability to proliferate, perhaps explaining why the human heart has little regenerative capacity.
The study, done in cell lines and mice, may lead to methods of reprogramming a patient's own cardiac myocytes within the heart itself to create new muscle to repair damage, said Dr. Robb MacLellan (pictured), a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and senior author of the study.
Unlike newts and salamanders, for example, human adults cannot spontaneously regrow damaged organs like the heart. However, recent research suggests that mammals do have the ability to regenerate the heart, but only for a very brief period, during about the first week of life.
If we had it once, MacLellan reasons, maybe it is possible to regain that ability.
Published recently, MacLellan's study suggests it might be possible to turn back the cellular clock to a time when cardiac myocytes had the ability to proliferate and regrow heart muscle.
"These salamanders and other lower organisms have the ability to de-differentiate cardiac myocytes, or take them back to an earlier, more primitive state, which allows them to reenter the cell cycle, creating new heart muscle," said MacLellan, who also is an associate professor of cardiology and physiology at UCLA. "In mammals, we've lost that potential. If we knew how to restore that, or knew the reason why adult myocytes can't do it, we could try to figure out a way to use nature's methods to regenerate the heart."
During human development, cardiac myocytes are made by progenitor stem cells, and they proliferate to form the heart. Once the heart is formed, the myocytes transform from immature cells into mature cells that can no longer proliferate. That's not so for newts and salamanders, whose cardiac myocytes can go back and forth between mature and immature, or primitive, states to proliferate and repair damage. Once damage is repaired, the cells revert back into mature cells.
MacLellan believes the reason humans can't do this is quite simple: When the myocytes are in a more primitive state, they're not as good at contracting, which is vital for proper heart function. Because humans are much larger than newts and salamanders, we need more heart contraction to maintain optimum blood pressure and circulation.
"The way we evolved, in order to maintain blood pressure and flow, we had to give up the ability to regenerate the heart muscle," MacLellan said. "The up-side is we got more efficient cardiac myocytes and better hearts. But it was a trade-off."
MacLellan said that by temporarily knocking down the proteins that block the cell-cycle mechanism, it may be possible to get adult cardiac myocytes to reenter the cell cycle and revert to a state where they can again proliferate. These therapies would need to be reversible so that the effects of the protein manipulation would eventually wear off once the damage is repaired. Then myocytes would become mature again and aid in contracting the regenerated heart muscle.
MacLellan currently is looking into using nanoparticles to deliver small interfering RNA to the heart to knock out the proteins that keep the myocytes mature.
When a heart attack occurs, oxygen is cut off to part of the organ, causing the cardiac myocytes to die and resulting in scar tissue. It's easy to locate the damaged area of the heart, and if a way could be developed to reprogram a patient's own myocytes, the protein-manipulation system could be injected into the damaged area, reverting the myocytes to their primitive state and replacing the dead muscle with new, living muscle, MacLellan said.
"People have been talking about the regenerative potential of these lower organisms for a long time and why this does not occur in humans," he said. "This is the first paper that provides a rationale and mechanism for why this happens."
There has been much talk of using human embryonic stem cells or reprogrammed induced pluripotent stem cells to regenerate the heart. However, it's unknown how much regeneration is possible and how much benefit would come from it.
"From my point of view, this is a potential mechanism to regenerate heart muscle without having to harvest or expand stem cells," MacLellan said. "Each person would be their own source for cells for regeneration."
Illustration: University of California, Los Angeles.
University of California, Los Angeles News Release (08/10/11)
Abstract (Journal of Cell Biology; Vol. 194, No. 3, 407-423 (08/08/11))