Advances in modern medicine have helped save countless people from heart attacks over the past 30 years. However, one consequence of survival is that more people -- over 23 million -- are living with heart failure, where the heart does not pump enough blood to supply the body's needs. Heart failure is a vicious cycle: Injury to the heart results in muscle loss, which leads to further damage. While medications can help improve heart function temporarily, they often fail in the long term. Thus, the problem still remains: How do we permanently repair the heart?
One approach to solving this problem involves introducing adult stem cells into the heart with the hope that they will regenerate or repair damaged tissue. Many clinical trials are being conducted to test this exciting idea, but unfortunately the vast majority of these trials are not showing significant benefits to patients. Adult stem cells simply may not have the potential to turn into new heart muscle cells.
So, if adult stem cells can't regenerate this lost muscle, is there something that can? The adult human heart is only half muscle; the other half is made of support cells called fibroblasts that help repair wounds and form scars around damaged tissue. In my lab, we decided to pursue using a heart's own cells to reverse the effects of heart failure -- we wanted to help a broken heart fix itself.
In a series of groundbreaking studies, Shinya Yamanaka, MD, Ph.D., a senior investigator at the Gladstone Institutes, identified the molecular factors that can convert fibroblasts into stem cells (termed induced pluripotent stem cells). These new types of stem cells have the capacity to turn into many other cell types, holding immense promise for regenerating damaged tissues all over the body. Indeed, this discovery was so game-changing that Dr. Yamanaka won the Nobel Prize for it in 2012.
Using the concept of changing one cell type to another, my team has been on a mission to find new ways to regenerate heart cells. We recently discovered that by introducing just three genes that nature uses to make heart cells in an embryo, we could convert fibroblasts directly into heart muscle cells in a lab dish, skipping the stem cell stage entirely and going straight from fibroblasts to beating heart cells. This was an extremely exciting finding, as it was the first time anyone had shown that by flipping a few key switches, one could create a functional heart cell from a different cell type.
The next step proved even more promising: when we introduced these three genes into the injured hearts of living mice, we were again able to convert fibroblasts into new heart cells, and these cells helped improve heart function, integrating with the old ones and beating in synchrony with the rest of the heart. Simply put, we were able to regenerate healthy heart muscle cells in an adult animal using its own cells, something that had never been done before.
We are now trying to use this gene therapy approach to regenerate larger hearts more similar to humans, like those found in pigs. We are also pursuing gene therapy as an avenue for treating patients, trying to bypass the need for introducing genes and instead use a cocktail of drug-like molecules to generate beating heart cells and regenerate damaged hearts.
The most encouraging aspect of this approach is that it may provide permanent restoration of function. Surgery or medications require multiple treatments and often carry additional drawbacks, but creating new heart muscle may last forever. If this type of regenerative medicine works in humans, it could completely change how we treat heart disease in the future.
This paradigm of harnessing cells in nearby areas of damage to replenish lost tissue is not just applicable to the heart; it may be useful in many other organs in the body that have support cells like fibroblasts. Indeed, other groups have taken our findings and begun to apply them to injuries in the spinal cord, the brain, and hearing loss.
It's important to keep in mind that we are still in the early stages of this research, and there is much work to be done. However, it appears we are on a path to the solution.
Stem cells offer great hope to treat a variety of diseases, but the strategy we are taking offers an alternative approach to regenerate organs. Specifically, we should look to the great potential of changing our own cells to repair damaged tissue; this could transform the future of medicine and would be the ultimate personalized medicine.