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May 15, 2001

Progenitor Cells Can Have Protective Effect Against Brain Trauma

Cell Transplants in Rats Restore Brain Function and Lessen Further Damage in The Brain

(Philadelphia, PA) - University of Pennsylvania researchers have found that by transplanting neural progenitor cells into rats with brain injuries they can restore brain function and lessen further brain damage. Their findings are the first to demonstrate the ability of progenitor cells, grown in culture, to restore cognitive and motor function while rescuing brain cells from the cumulative effects of traumatic brain injury.

The results of the research, led by Tracy K. McIntosh, PhD, of the University of Pennsylvania School of Medicine, is presented in the May issue of the Journal of Neurosurgery.

"Stem cell transplants are currently of interest because of the potential they have for treating brain injuries in humans," said McIntosh, professor in the departments of Neurosurgery, Bioengineering, and Pharmacology and director of Penn's Head Injury Center. "In this study we have determined how progenitor cells - a more developed type of stem cell - cannot only restore function, but counteract the secondary injuries that result from brain trauma."

Unlike stem cells, which are completely unspecialized, progenitor cells have begun the path to specialization. In this study, the stem cells used have become progenitor brain cells, although they have not yet developed into a specific type of brain cell. The researchers found that the progenitor cells were able to survive in the hostile environment of the injured brains and actually promote the reconnection of brain pathways that were destroyed during trauma. Using tests to determine cognitive ability and motor skills, rats with the transplanted progenitor cells recovered substantially better than rats that did not have the transplanted cells.

The researchers used two different types of cultures of the same progenitor cells. One type remained 'naïve;' that is, they had not been altered, while the other had been transfected with a gene to produce Nerve Growth Factor (NGF). As the name suggests, NGF is an enzyme that induces nerve cells to grow.

"We had originally hypothesized that the NGF-producing cells would be more capable of regenerating brain function," said McIntosh. "We were surprised to find that, in terms of nerve growth, both types of cells performed equally well."

The NGF-producing cells, however, had an additional effect - they protected against further damage in the brain.

The destruction of brain tissue does not stop after the initial head impact. Cells in the brain weaken and continue to die from the cumulative effects of the injury in a process called apoptosis, a series of internal reactions that causes the cells to die. The rats that received the NGF-producing cells retained a significant amount of brain cells after transplant than the rats that received just the naïve cells.

According to McIntosh, in addition to promoting nerve growth, NGF also induces brain cells to produce more antioxidant enzymes, which remove the free radicals that may trigger apoptosis. "The NGF-producing cells provide cells with an added resistance against the dangerous environment of an injured brain," said McIntosh. "And so we have the combined strength of a growing progenitor cell and a nice supply of a molecule that ensures that the cells continue to thrive."

The research presented in this study is a collaborative effort between researchers at Penn and counterparts in Sweden and Spain, with whom McIntosh began an association as a Fullbright Fellow on sabbatical in Europe. Other contributing researchers include Tadeusz Wieloch, PhD, Anders Bjorklund, PhD, Gustav Mathiasson, PhD, and Gregor Tomasevic, PhD, from Lund University, and Alberto Martinez-Serrano, PhD, of the Autonomous University of Spain. Other Penn researchers include Matthew F. Phillips, MD, Philipp Lenzlinger, MD, Grant Sinson, MD, and M. Sean Grady, MD.

For the last decade, McIntosh and his colleagues at Penn's Head Injury Center have been investigating the effects of brain injury and possible treatments. Each year, approximately 100,000 people die from traumatic brain injuries, and 500,000 more are permanently disabled. Every 15 seconds, someone, usually a young person, suffers from a brain injury.

"Sadly, it is an epidemic that most people do not realize exists," notes McIntosh, "and to date, there is no clinical treatment that can effectively treat the damage."

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The University of Pennsylvania Health System is distinguished not only by its historical significance - first hospital (1751), first medical school (1765), first university teaching hospital (1874), first fully integrated academic health system (1993) - but by its position as a major player on the world stage of medicine in the 21st century. Penn ranks second among all American medical schools that receive funds from the National Institutes of Health, perhaps the single most important barometer of research strength.




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