Some organisms have a remarkable capacity for regenerating tissue. If a fish or salamander suffers heart damage, for instance, their cells are able to divide and successfully repair the injured organ. Imagine if you could do the same.
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.
"Because so many adult cells can't divide, your body can't replace cells that are lost, which causes disease," explaines senior investigator. "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.
In a new study published in the scientific journal Cell, the team finally reached this long-sought goal. They 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. 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.
Authors show that overexpression of cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1 efficiently induced cell division in post-mitotic mouse, rat, and human cardiomyocytes. Overexpression of the cell-cycle regulators was self-limiting through proteasome-mediated degradation of the protein products.
"We discovered that when we increased the function of these four genes at the same time, the adult cells were able to start dividing again and regenerated heart tissue," said first author of the study. "We also showed that, after heart failure, this combination of genes significantly improves cardiac function."
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.
In vivo lineage tracing revealed that 15%–20% of adult cardiomyocytes expressing the four factors underwent stable cell division, with significant improvement in cardiac function after acute or subacute myocardial infarction.
"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," said the senior author. "Of course, in human organs, the delivery of genes would have to be controlled carefully, since excessive or unwanted cell division could cause tumors."
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. Chemical inhibition of Tgf-β and Wee1 made CDK1 and cyclin B dispensable.
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.
"Heart cells were particularly challenging because when they exit the cell cycle after birth, their state is really locked down--which might explain why we don't get heart tumors," said the senior author. "Now that we know our method is successful with this difficult cell type, we think it could be used to unlock other cells' potential to divide, including nerve cells, pancreatic cells, hair cells in the ear, and retinal cells."
This could lead to a powerful regenerative approach to treat not only heart failure, but also brain damage, diabetes, hearing loss, and blindness. And one day, the human might just outperform the salamander.
Genes that enable adult cardiac cells to divide and multiply identified!
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