NEW YORK (March 22, 2005) -- The discovery by Weill Medical College of Cornell University researchers that a specific type of human fetal stem cell can co-differentiate simultaneously into both muscle and blood vessel cells may unlock the door to therapies that replace damaged tissue in the heart and other organs.

Heart attack and other events can destroy cardiac muscle and the surrounding vasculature (blood vessels), so effective heart repair requires concurrent replacement of both these types of tissues.

The new finding -- published in this monthÕs issue of Circulation -- moves us one big step closer to that goal, the investigators say.

"This discovery comes at a time when research into these types of stem-cell-based regenerative therapies have faced major hurdles," said Dr. Shahin Rafii, Arthur B. Belfer Professor of Genetic Medicine and newly announced Howard Hughes Medical Institute (HHMI) investigator at Weill Cornell Medical College in New York City.

"Poor results from previous work, where donor stem cells were injected directly into the damaged heart tissue, suggested that something was missing -- either the conditions in the surrounding tissue weren't suitable, or we needed to find a more pluripotent stem cell that could readily co-differentiate into both muscle and blood vessels in order to initiate rapid revascularization of the regenerating heart tissue," he explained. "We may be closer now to solving that problem."

Dozens of papers have confirmed the potential of bone-marrow-derived stem cells to develop into cardiac tissue cells, and for a while it looked like purified stem cells from adult bone marrow might do the trick.

However, those hopes were dashed last spring, when a group of researchers found the ability of these stem cells to incorporate into ailing heart tissue was much less robust than originally thought.

"So, it was 'back to the drawing board' for this type of stem-cell research," said study lead author Dr. Sergey V. Shmelkov, a postdoctoral fellow working in Dr. Rafii's lab.

Fortunately, for almost five years, the Weill Cornell team had evidence that a specific type of stem cell -- bearing a surface antigen called CD133 -- was unusually adept at differentiating (developing) into a myriad of organ-specific cell types.

While cells bearing this CD133 biomarker are very rare in adult tissues, they are particularly abundant in the fetal liver.

"We wondered if, given the right conditions, these cells might fulfill the requirement of growing into both myocytes (muscle cells) and angiogenic (blood-vessel-wall) cells, both of which are needed for efficient heart repair," Dr. Shmelkov explained.

Using human fetal liver tissues, the Weill Cornell team isolated CD133+ stem cells, then bathed them in a culture rich in growth factors and other biochemicals.

"Working in close collaboration with Dr. Barbara Hempstead and Dr. Jay Edelberg here at Weill Cornell, we also identified specific growth factors that promote CD133+ stem-cell differentiation. These biochemical growth factors include vascular endothelial growth factor-A (VEGF-A) and brain-derived nerve growth factor (BDNF)," Dr. Rafii explained. "The very presence of these growth factors helped push the stem cells to co-differentiate simultaneously into both muscle and endothelial cells."

"The process was much enhanced in the presence of these specific growth factors, generating relatively large amounts of both types of cells," said Dr. Hempstead, whose recent work with Dr. Pouneh Kermani had suggested that BDNF plays a critical role in inducing new blood vessel formation.

"Importantly, only stem cells with the CD133 antigen developed into endothelial blood vessel cells and myocytes," Dr. Rafii said. "Stem cells without this surface antigen failed to do so."

Testing those results in an animal model, the researchers then injected cells derived from both CD133+ and CD133- liver stem cells into mice.

"Remarkably, the CD133+ derived cells developed into pulsating vascularized cardiomyocytes -- muscle cells specific to cardiac tissue, whereas the CD133- derived cells did not," explained Dr. Edelberg, who has helped pioneer the development of mouse models that researchers can use to test this type of xenograft muscle formation.

"This is really an important discovery," Dr. Shmelkov said, "because it proves that, given the right micro-environmental clues, we can encourage the regrowth of vascularized heart tissue. Muscle cells need vasculature to grow and survive, so we need to find stem cells capable of forming both myocytes and angiogenic cells. We think we've found them."

He stressed that, because areas of cardiac damage often lack essential biological cues critical for stem-cell differentiation, doctors in the future might first give these angiomyogenic stem cells a "jump-start" in the lab (a process known as "pre-condition") before transplanting them to the site of injury within the heart.

Other roadblocks remain. Because of the potential for immuno-rejection, cells isolated from the patient's own body remain the best choice, rather than cells obtained from fetal tissue.

"That's why we're currently looking into whether human adult livers might bear traces of CD133+ stem cells, and we're also testing the possibility that stimulation of bone marrow stem cells with these same growth factors might also generate myocytes and angiogenic cells," Dr. Shmelkov said.

The team is also investigating whether stem-cell specific CD133 promoters, previously discovered by the same group, can serve as a kind of chemical "tag," allowing researchers to track the availability and activity of these cells in particular organs throughout the body.

"All of these findings are re-igniting interest in using these biochemically activated stem cells to regenerate vascularized tissue," Dr. Rafii said. "Some of our research may even help find new sources of expandable CD133+ stem cells within umbilical cord blood or adult bone marrow, livers, or other organs."

"Each year thousands of adults succumb to heart attack. We hope our study will provide the impetus to initiate clinical trials that can help ease the tremendous physical and socio-economic burden caused by vascular diseases," he added.

The study was supported by grants from the National Heart, Lung, and Blood Institute.

Co-researchers included Dr. Sarah Meeus, Dr. Pouneh Kermani, Dr. William K. Rashbaum, Dr. Marilee A. Hanson, Dr. Sergio Dias, Dr. Jason T. Jacobson, Nelson Moussazadeh, William J. Lane, Ryan St. Clair, and Kathryn A. Walsh -- all of Weill Cornell Medical College.

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