Weill research: Growth factor boosts cell production in damaged hearts

By Jonathan Weil

NEW YORK, N.Y. -- Weill Cornell Medical College researchers have discovered that injecting a growth factor called PDGF-AB along with bone marrow cells into the heart can cause new heart cells to grow in scar tissue. The research, conducted in an animal model, has just been published in the "Online First" section of Circulation Research (March 19 print and online issue).

The finding may one day lead to better treatments for heart attack, which can cause portions of the heart to die and form scar tissue. Many researchers are trying to use stem cells -- which are immature cells found in bone marrow -- to replace cells that are dead or damaged after a heart attack.

Edelberg

Dr. Jay Edelberg and colleagues report that they added PDGF-AB (platelet-derived growth factor-AB) to mouse bone marrow cells in the laboratory and doubled the number of heart cells produced by the marrow.

And the growth factor dramatically boosted the number of heart cells, known as cardiac myocytes, in rats with heart damage similar to that seen in human heart-attack patients. Myocytes are cells that can beat on their own, and when they connect with each other correctly in the heart, they beat as one unit.

When saline solution (as a control) was injected into the heart, no new myocytes formed in the scar tissue. Adding a combination of PDGF-AB and bone marrow cells doubled or quadrupled the number of cardiac myocytes in the heart compared with injection of bone marrow cells or PDGF-AB alone.

"The most important thing is that we now have a new way of being able to enhance the generation of cardiac myocytes, and we can do it both in tissue culture and in the heart, and that offers us great promise," said Edelberg, assistant professor of medicine in the Greenberg Division of Cardiology at Weill Cornell Medical College and assistant attending physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

In the past four to five years, a number of studies have shown that, in the laboratory, stem cells in bone marrow can produce heart cells. And other studies have suggested that delivering bone marrow cells to the heart of a heart attack patient may result in improvement.

"But no one has actually been able to link the two of those things together," said Edelberg.

"We found that when we injected the bone marrow cells straight up into the hearts of the rats, we got a lot of blood vessel cells and a couple of cardiac myocytes, and that was similar to what others have found," he said. "When we mixed bone marrow cells with the extra growth factor, we suddenly got a lot more cardiac myocytes."

However, more study is needed before such a treatment can be tried in human patients. Although the PDGF-AB boosted heart-cell production, the cells seemed to grow in a disorganized fashion and did not hook up correctly with neighboring heart cells.

"The bone marrow-derived cells made a lot of cardiac myocytes and that's great. The problem is we made so many of them, so quickly, they did not make all the functional connections they should have made," said Edelberg. "We may be able to correct this by giving them more time or directing their growth. We have to make sure they go in all the right places at the right time."

A disorganized cluster of heart cells could contribute to heart arrhythmias, so the researchers are working on a way to get cells to grow in a specific pattern.

"We think the blood vessels will give us the natural patterning, so we are focusing a lot on that and pushing in that direction," Edelberg said.

What's more, PDGF-AB is not yet appropriate for use in patients because it can boost the growth of smooth muscle cells, a type of cell that could block arteries. This could pose a problem if given directly to heart disease patients who already have clogging of the arteries.

"We are trying to develop approaches that are more specific so that it will induce just cardiac myocytes," said Edelberg.

The researchers ultimately hope to find an oral drug that could enhance the body's natural ability to mobilize bone marrow stem cells and produce cardiac myocytes. Injecting growth factor and bone marrow cells directly into the heart is impractical for treating most heart attack patients.

The study's co-authors include Weill Cornell's Dr. Munira Xaymardan (lead author), Dr. Lilong Tang, Leze Zagreda, Dr. Benedetta Pallante, Dr. Jingang Zheng, Joseph Chazen, Andrew Chin, Inga Duignan, Dr. Patrick Nahirney, Dr. Shahin Rafii and Dr. Takashi Mikawa.

The study was funded by grants from the National Institutes of Health, the Rockefeller Brothers Charles E. Culpeper Scholarship Program, American Heart Association and the Atrovastatin Research Awards Program.

The article is available online at http://circres.ahajournals.org/onlinefirst.shtml.