Key protein could help to keep the heart in rhythm.
Researchers have managed to restore heart function by transplanting muscle stem cells into damaged mouse hearts. Their results suggest that the technique could one day be used to heal heart tissue in humans.
Similar transplants have been tried before in both mice and humans, but have met with little success. Although the grafts sometimes improved the function of the heart, they also raised the risk of abnormally fast heartbeats, in a disorder called ventricular tachycardia. Ventricular tachycardia is the main cause of sudden death in patients who have had a heart attack, killing about 15% of patients within three years of their attack.
?It?s an enormous clinical problem that is clearly unsatisfactorily treated by our available tools,? says Richard Lee, a researcher and cardiologist at Brigham and Women?s Hospital in Boston, Massachusetts. ?A great number of things that we?ve tried to do to suppress arrhythmias in humans have instead caused them.?
Heart attacks in humans are typically caused by a gradual loss of blood flow that slowly starves cardiac cells of nutrients. As the cells die, heart function declines.
Researchers have long hunted for a way to either prevent or reverse the effects of heart failure by replacing the damaged heart cells. Early results showed that injecting injured regions of the heart with skeletal-muscle stem cells or even bone-marrow cells could restore some function.
Exactly how this works is unclear: some say that the muscle stem cells contract just like heart-muscle cells, helping the heart to beat. Others propose that the transplanted cells stiffen the cardiac wall, or perhaps secrete compounds that aid neighbouring, functional cardiac muscle cells. Whatever they do, one thing is clear: both cell types sometimes improve the heart?s ability to beat, but they also disrupt its beating rhythm.
So Michael Kotlikoff of Cornell University in Ithaca, New York, and Bernd Fleischmann of the University of Bonn in Germany, and their colleagues, tried to transplant a different type of cell, called embryonic cardiac-muscle cells. These cells, they found, coupled physically with the surrounding heart tissue and could exchange electrical signals with their new neighbours ? signals that are used to keep a heart beating in time. The result was a well-behaved heart, they report in Nature1. Relatively few transplanted cells were required to get the effect.
So why were the embryonic cells better at blending in with their surroundings than the adult muscle cells? The researchers thought one explanation might be that both embryonic cells and adult heart cells have higher expression of a protein called connexin 43, which is important for forming connections between cells. Connexin 43 is expressed at lower levels in adult muscle stem cells.
To test whether connexin 43 was indeed the key factor, they team tried using adult muscle stem cells that had been forced to express the protein. This produced similarly good results. ?If you make these cells express connexin 43, they correct or reverse the vulnerability to arrhythmia,? says Kotlikoff. This could liberate future researchers from relying on embryonic tissue, which can be more difficult to acquire.
The technique will have to surmount a number of technical hurdles before it can be used as therapy. ?It?s very exciting to have a new concept like this, but one has to be extremely cautious about where it?s going to go clinically,? says Lee. ?Arrhythmia has been particularly vexing. We have really a lot of experience with things that look like they will help in animals, but when we get them into humans they don?t.?
Kotlikoff notes that the team has evaluated performance of the transplants for only about two weeks ? not long enough to ascertain whether the grafts will be stable in the long term. And the damaged heart tissue in their mice was concentrated in a specific region of the heart, unlike the mosaic of live and dead cells found in human hearts.
Roell, W. et al. Nature 450, 819?824 (2007).