Working on Regeneration of Pacemaker Tissue

Given greater control over cells and tissue growth there are potentially all sorts of ways in which researchers could augment function for healthy people or compensate for loss due to illness and aging. One near term prospects is the ability to reprogram existing superfluous cells in an organ in order to replace small but crucial cell populations that are diminished by aging. Examples include the dopamine-generating neurons lost in Parkinson's disease, but every older individual also suffers a similar loss of these cells due to the damage of aging, just not to the same level. Parkinson's, like many age-related diseases, is a consequence of the rapid progression of a usually slower process that happens to everyone. Other examples include the loss of some of the specialized cell populations in the kidneys, liver, and pancreas. In most of these cases, there are nearby cells in the organ that could in principle be reprogrammed without consequence, as they will either be replaced fairly quickly or their loss is inconsequential.

In the article linked below the heart is the focus, and cardiac pacemakers are the small cell population of interest. One of the near future goals for cell therapy is to eliminate the need for artificial pacemakers and their numerous drawbacks for individuals suffering forms of dysregulation or loss of pacemaker tissue in the heart. Instead the natural population of pacemaker cells would be augmented and guided to better function. This seems a very plausible goal for the next decade, but work similar to that quoted below has been taking place for the past ten years, and there is a way to go yet before human trials will begin:

Next Generation: Biological Pacemakers

Scientists have been investigating ways to biologically recreate the natural pacemaker cells - a collection of specialized impulse-generating heart cells called the sinoatrial node. One approach has been to express the protein TBX18 in heart muscle cells. TBX18 is a transcription factor that drives development of pacemaker cells in the vertebrate embryo, but it can also directly convert adult heart muscle into pacemaker cells. Indeed, such reprogramming has been achieved in the guinea pig heart, where TBX18 expression has been shown to restore pacemaker function. For such an approach to be applicable to humans, however, the technique needed to be scaled up.

Twelve pigs had their own natural pacemakers experimentally destroyed. They then had back-up electronic pacemakers installed, but also received injections of adenovirus vectors containing the TBX18 gene into their heart muscle. The injected cells adopted the morphology and markers of pacemaker cells and, more importantly, acted like them. After just two days, TBX18-injected pigs had higher heart rates compared with control animals, and after five days they had a less than 1 percent reliance on their electronic pacemakers, while control animals relied on their electronic pacemakers between 8 percent and 40 percent of the time.

"It's an impressive piece of work that shows proof-of-concept, in a large animal, that we could actually harness the potential to convert one cell to another to cure disease." The reprogrammed pacemakers exhibited natural rises and falls in heart rate over day and night cycles as well as increased heart rate during physical exercise. "We're quite excited about that, because we think we can recreate the normal pacemaker function rather than fixing something artificially. Electronic devices cannot really follow the human physiology."

The team monitored the pigs for two weeks after injections and found that the activity of the induced pacemaker cells peaked at day eight and then slowly declined. This was not a surprise because adenovirus-infected cells tend to be cleared from the body. Such short-term reprogramming would be fine for patients requiring a temporary alternative to electronic devices, such as those undergoing treatment for pacemaker-related infections. But for long-term reprogramming, an alternative vector would be necessary.


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