The heart is not a very regenerative organ in mammals, its cells comparatively reluctant to multiply to make up losses or repair injuries - and mammals are a good deal less regenerative than many other species. Zebrafish can regenerate entire missing sections of the heart to completely restore normal function without scarring, for example. Is it possible for the biochemistry of mammals to be adjusted so as to approach this feat? If so, this could make a sizable difference to the trajectory of heart disease and heart failure in later life, even though it doesn't address the root causes of age-related cardiovascular disease. Researchers here report on an important step in this direction, inducing replication in heart muscle cells, and showing that their approach results in significant regeneration in rodents.
In the embryo, human heart cells can divide and multiply, allowing the heart to grow and develop. The problem is that, right after birth, cardiomyocytes (heart muscle cells) lose their ability to divide. The same is true for many other human cells, including those of the brain, spinal cord, and pancreas. "If we could find a way to get these cells to divide again, we could regenerate a number of tissues." For decades, the scientific community has been trying to do just that, with limited success. Until now, attempts have been ineffective and poorly reproducible.
Researchers have now developed the first efficient and stable method to make adult cardiomyocytes divide and repair hearts damaged by heart attacks, at least in animal models. The team identified four genes involved in controlling the cycle of cell division, these being cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1. They found that when combined - and only when combined - these genes cause mature cardiomyocytes to re-enter the cell cycle. This results in the cells dividing and rapidly reproducing.
The scientists tested their technique in animal models and cardiomyocytes derived from human stem cells. They used a rigorous approach to track whether the adult cells were truly dividing in the heart by genetically marking newly divided cells with a specific color that could be easily monitored. They demonstrated that 15-20 percent of the cardiomyocytes were able to divide and stay alive due to the four-gene cocktail. "This represents a considerable increase in efficiency and reliability when compared to previous studies that could only cause up to 1 percent of cells to divide."
To further simplify their technique, the team looked for ways to reduce the number of genes needed for cell division while maintaining efficiency. They found they could achieve the same results by replacing two of the four genes with two drug-like molecules. The researchers believe that their technique could also be used to coax other types of adult cells to divide again, given that the four genes they used are not unique to the heart.