A team of Harvard Stem Cell Institute researchers at Massachusetts General Hospital (MGH) with HSCI colleagues at Harvard’s School of Engineering and Applied Sciences (SEAS) have taken a giant step toward the possibility of using human stem cells to repair damaged hearts.
In a report published in Science, the team led by Kenneth Chien, MD, PhD, head of the HSCI Cardiovascular Disease Program, reports identifying a human cardiac master stem cell and using it to create a functioning strip of ventricular muscle using technology developed by Kevin Kit Parker, PhD, of SEAS and Harvard’s Wyss Institute for Biologically Inspired Engineering.
“This is the beginning of making heart parts for heart disease,” Chien said.
This latest finding raises the possibility of someday using induced pluripotent stem cell (iPS) technology to take a skin cell from a patient with heart disease and use it to generate muscle tissue to repair the diseased heart – avoiding the need to suppress the immune system and the possibility of rejection, a major issue in organ transplantation.
“This finding is an initial step in moving beyond heart stem cell biology towards a different level – finding a rare cardiomyogenic cell from embryonic stem cells that can proliferate on its own and could potentially be therapeutic. This moves us closer to heart stem cell therapy,” Chien explained. “The beauty of the system our team has developed relates to the almost pure population of the exact cells, ventricular heart cells, which we’re trying to replace in a damaged heart, and then expanding and assembling them into a functioning strip of pure ventricular muscle. That has not been done to my knowledge.”
We’ve “been able to take these very rare populations of muscle progenitors that were isolated because the cells were color coded,” Chien explained. “We look for the cells that have a mixed color read out. We’ve been able to take those cells and put them one layer thick on something that is almost like Saran Wrap. When they contract, they flex the film. We have the pure cells, they can be expanded, and they can make a fully functional strip of muscle.”
HSCI Affiliate Faculty Ibrahim Domian, MD, PhD, who was a postdoctoral fellow in Chien’s lab and is now starting his own lab at MGH, is first author on the Sciencepaper.
Parker, whose lab developed the technology that produces a strip of muscle from the cardiac cells, said "We try to develop technologies that are cell-agnostic; they can work with Ken’s cardiac progenitors, or anyone else’s stem cells. These techniques are not limited to cardiac cells, or even to stem cells for that mater.”
“This is the latest in a chain of scientific discoveries that have come out of our lab here at Mass General and the Harvard Stem Cell Institute that have been a collaboration of physicians, scientists, and bioengineers,” Chien said. “And for the first time, we report the identification of a cell that could be viewed as perhaps an optimal cell type to promote cardiac muscle regeneration because the cells that we use come from embryonic stem cells and then have been induced to form an intact strip of functioning ventricular muscle. So we’ve gone from the most basic form of undifferentiated stem cell to ventricular muscle – and that’s the type of muscle in the heart we’re trying to regenerate,” Chien said.
“What we think we have right now are the exact cell types to do this type of repair,” said Domian. “One way or another, we have to get to three dimensions. The amazing thing about these strips we have now is that it is generating the right amount of force, but as you want to generate more force, you have to increase the thickness of the strip, and it has to have its own blood supply. There are two ways you could do this – rely on tissue engineering to produce a strip such as that, or find a way to use the natural architecture of the heart to regenerate the muscle. We’re now working hard in our lab and with Kit Parker to see how we could produce the thicker strip.”
Delivering cells to the body might require a number of approaches, Chien said. One way might be to incorporate the cells into a gel of some kind, which could be applied to the damaged muscle. Another might be to simply inject the cells into the damaged tissue, hoping that they would proliferate and create new muscle. In Chien’s view, novel technology for cell delivery will be required in either case.
Over the past two years, Chien and his team have published a series of “leap-frogging” studies, first making a discovery in mice, then replicating it in human embryonic stem cells, then taking the next step in mice, then moving on to to human cells. Next comes the attempt to actually repair cardiac damage in animals and then on to clinical studies in the next 5 years.
“In mice we’re in a position to attempt the repair right now,” Domian said. “We can cause a heart attack, and then look for ways to repair the tissue. The simplest way is to inject the cells into the tissue – we can do that right now in mouse. If that doesn’t work, we have to rely on other technologies. But this is direct proof of concept that a similar approach will work with human ES cells.”
“Now we’re actually in the core of the next level of challenges that face all of regenerative medicine. In essence, I think we’re moving quite quickly now from stem cell biology all the way through towards regenerative medicine,” Chien said.
Genetic modification of the mouse embryo allowed for the color-coding of different parts of the heart with green,red,or both green and red (shown in yellow).
Cardiac progenitors were used to engineer 2-dimensional cardiac tissue into a muscular thin film (MTF). To measure contractility,the MTF was fixed as a cantilever on one end and the contracting cells bent the MTF toward the cell-side during contraction.The force generated by this ESC-derived MTF was similar to MTFs engineered from neonatal cardiac muscle cells.