Modern medicine often involves the development of a drug or treatment outside the body, which is then given to a patient to fix, improve or even prevent their condition. But what if you could regenerate or heal the body using the cells and tissue already inside a patient?
Scientists at the Gladstone Institutes are pursuing such a strategy for heart disease. In a CIRM-funded study published today in the journal Cell, the team identified four genes that can stimulate adult heart muscle cells, called cardiomyocytes, to divide and proliferate within the hearts of living mice. This discovery could be further developed as a strategy to repair cardiac tissue damage caused by heart disease and heart attacks.
Regenerating the Heart
Heart disease is the leading cause of death in the US and affects over 24 million people around the world. When patients experience a heart attack, blood flow is restricted to the heart, and parts of the heart muscle are damaged or die due to the lack of oxygen. The heart is unable to regenerate new healthy heart muscle, and instead, cardiac fibroblasts generate fibrous scar tissue to heal the injury. This scar tissue impairs the heart’s ability to pump blood, causing it to work harder and putting patients at risk for future heart failure.
Deepak Srivastava, President of the Gladstone Institutes and a senior investigator there, has dedicated his life’s research to finding new ways to regenerate heart tissue. Previously, his team developed methods to reprogram mouse and human cardiac fibroblasts into beating cardiomyocytes in hopes of one day restoring heart function in patients. The team is advancing this research with the help of a CIRM Discovery Stage research grant, which will aid them in developing a gene therapy product that delivers reprogramming factors into scar tissue cells to regenerate new heart muscle.
In this new study, Srivastava took a slightly different approach and attempted to coax cardiomyocytes, rather than cardiac fibroblasts, to divide and regenerate the heart. During development, fetal cardiomyocytes rapidly divide to create heart tissue. This regenerative ability is lost in adult cardiomyocytes, which are unable to divide because they’ve already exited the cell cycle (a series of phases that a cell goes through that ultimately results in its division).
Deepak Srivastava (left) and first author Tamer Mohamed (right). Photo credits: Diana Rothery.
Unlocking proliferative potential
Srivastava had a hunch that genes specifically involved in the cell division could be used to jump-start an adult cardiomyocyte’s re-entry into the cell cycle. After some research, they identified four genes (referred to as 4F) involved in controlling cell division. When these genes were turned on in adult cardiomyocytes, the cells started to divide and create new heart tissue.
This 4F strategy worked in mouse and rat cardiomyocytes and also was successful in stimulating cell division in 15%-20% of human cardiomyocytes. When they injected 4F into the hearts of mice that had suffered heart attacks, they observed an improvement in their heart function after three months and a reduction in the size of the scar tissue compared to mice that did not receive the injection.
The team was able to further refine their method by replacing two of the four genes with chemical inhibitors that had similar functions. Throughout the process, the team did not observe the development of heart tumors caused by the 4F treatment. They attributed this fact to the short-term expression of 4F in the cardiomyocytes. However, Srivastava expressed caution towards using this method in a Gladstone news release:
“In human organs, the delivery of genes would have to be controlled carefully, since excessive or unwanted cell division could cause tumors.”
First stop heart, next stop …
This study suggests that it’s possible to regenerate our tissues and organs from within by triggering adult cells to re-enter the cell cycle. While more research is needed to ensure this method is safe and worthy of clinical development, it could lead to a regenerative treatment strategy for heart failure.
Srivastava will continue to unravel the secrets to the proliferative potential of cardiomyocytes but predicts that other labs will pursue similar methods to test the regenerative potential of adult cells in other tissues and organs.
“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. 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.”
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