In heart disease, cardiac muscle gradually dies off and, with little or no way to regenerate those cells, that can ultimately lead the heart to fail. But scientists reporting in the August 6th issue of Cell, a Cell Press publication, might have found a way to fix those losses. They've devised a three-ingredient molecular cocktail that transforms fibroblasts - structural cells that the heart is chock full of - directly into beating heart cells.
"In the cardiac field, we've been trying for over 20 years to figure out how to convert non-muscle cells into cardiac muscle," said Deepak Srivastava of the University of California, San Francisco. "Now we've found a way to change fibroblasts - which make up 50 percent of all heart cells -- into new cardiomyocytes."
Researchers had been searching for a master regulator of cardiac muscle - a single ingredient that could drive the formation of heart muscle. That kind of master had been found for skeletal muscle in the 1980s, but finding the same for the heart turned out to be a bigger challenge.
More recently, Srivastava and his colleagues were inspired by the discovery that fibroblasts could be reprogrammed with a combination of factors into cells that look and act a lot like embryonic stem cells, so-called induced pluripotent stem (iPS) cells. Perhaps they could find a cocktail that would reprogram fibroblasts into cardiac muscle, without having to revert to a stem cell state in the process.
The researchers started with 14 factors known to play a role in heart development. That fairly complex cocktail showed small but sure signs of working. They then whittled that down, removing factors one by one, until they found three factors that did the trick.
In fact, Srivastava said, that minimal cocktail was a lot more efficient in producing new cardiac muscle cells than the more comprehensive one they started with. "Unlike iPS reprogramming, wich is very inefficient, we get 20 percent of fibroblasts to turn to cardiomyocytes," he said. "That's pretty robust." By comparison, the iPS cocktail successfully transforms just 0.1 percent of fibroblasts, he added.
The initial reprogramming happens within three days. After that, the cells gradually take on the characteristics of cardiac muscle over the course of several weeks, as they turn into fully reprogrammed, beating heart cells. The same three factors could also transform fibroblasts taken from skin, they report.
When fibroblasts treated with the three factors were transplanted back into mouse hearts just one day later, they still differentiated into cardiac muscle. "That gives us encouragement that cells sitting in the heart could be reprogrammed without taking them out," Srivastava said.
The current recipe for cardiac muscle relies on inserting three genes encoding transcription factors into heart cells with a virus. Ultimately, Srivastava says they would like to replace that method with one using small molecules or other secreted proteins. Those could perhaps be placed into a stent inserted into the heart, where they could drive the growth of new heart muscle. "That's our long term goal," Srivastava said.
The researchers demonstrated that the fibroblasts in their study didn't first have to return to a stem cell state. Rather, they hopped directly from one adult identity to another. That could be an advantage over using iPS or embryonic stem cells to regenerate heart cells, Srivastava explained. In the case of stem cells, "it's a problem if there are stray cells that haven't fully differentiated. They might have the ability to turn into an unwanted cell type; they could grow into a tumor or a cell that just doesn't belong."
And there is another plus: heart muscle cells derived from stem cells for some reason don't mature into cells with the electrical activity characteristic of true adult cardiac muscle. The new method, on the other hand, produces cells that look and act like bona fide adult ventricular muscle cells.
Now, the search is on for small molecules that could mimic the effects of the new cocktail and serve as heart-regenerating drugs - an approach that Srivastava notes has worked for iPS cells.