University of South Florida
"What we found was interesting, phenomenal really," says Dr. Cesario V. Borlongan, neuroscientist and lead author of the study published in the October issue of the American Heart Association journal, Stroke.
Researchers first gave the drug, mannitol, to provide temporary passage through the blood-brain barrier then transfused human umbilical cord blood cells into a stroke animal model. When used in the first hours and days following a stroke, stroke size decreased by 40 percent and resulting disability was significantly reduced.
"We have two potential routes of delivery, intravenously through the jugular vein or directly transplanting the cells into the brain," says Dr. Borlongan. Initial studies comparing the two approaches showed the intravenous approach ineffective until researchers added mannitol.
"Intravenous delivery of (human umbilical cord blood cells) poses an efficient and non-invasive cell therapy for (central nervous system) disorders characterized by a narrow therapeutic window," the researchers write. "A multi-drug treatment for stroke may be realized via a cell-based therapy that involves routine clinical IV infusion of stem/progenitor cells allowing the biological release of a cocktail of trophic factors into the brain."
Although no evidence could be found of the low-dose umbilical cord blood stem cells themselves in the brain three days after the treatment, evidence of neuroprotection was clear, Dr. Borlongan says. "The critical factors we have seen elevated in this stroke animal model are the neurotrophic factors."
"This is an important finding because it shows that umbilical cord blood cells do not have to become new brain cells to protect the brain," says Dr. Paul R. Sanberg, neuroscientist at the University of South Florida and a co-author on the study. Human umbilical cord blood stem cells used for the study were obtained from Saneron CCEL Therapeutics, Inc., in Tampa, Fla., a USF spin-off company researching clinical applications for cord blood cells.
An article in the same issue of Stroke by the USF researchers led by Dr. Alison Willing, neuroscientist, shows that 10 times the number of stem cells or more would be needed to produce similar results if cells were given intravenously without any help crossing the blood-brain barrier.
The MCG-led study used 200,000 umbilical cord blood cells and a low dose of mannitol, a sugar alcohol and diuretic whose uses include helping chemotherapeutic agents reach the brain. The USF study showed a dose-response relationship with significant recovery in behavioral performance when 1 million or more cells were given, Drs. Willing and Sanberg and their colleagues report.
"The advances we are seeing here are with mannitol, you can deliver a smaller number of cells and it can protect against stroke," Dr. Borlongan says. "It can reduce the size of infarction; it can lead to behavioral improvement," an important implication for clinical applications because stem cells are difficult to harvest. By using mannitol or similar drugs, it may be possible to treat stroke patients in the future with cells from only a few umbilical cords, adds Dr. Sanberg.
The Stroke paper also explored how stem cells provide neuroprotection. The researchers speculated it was by providing the large influx of nourishing neurotrophic factors secreted by the stem cells. To test that theory, they looked at what happened when they used antibodies that negated some of the factors. "When we blocked the neurotrophic factors, it blocked the positive effect," Dr. Borlongan says.
The study also looked at mannitol as a therapy because of previous reports it reduces cerebral swelling and stroke damage. Researchers found that at the same low dose used to accompany the stem cells, mannitol alone was ineffective. "The dosage we are using is probably 10 times lower than the one showing mannitol itself to be protective," Dr. Borlongan says. But those higher doses come with higher risks as tight cell junctions that prevent many molecules from reaching the brain relax for longer periods, leaving the brain susceptible to problems such as infection.
Drs. Borlongan and Willing are consultants and Dr. Sanberg is cofounder of Saneron CCEL Therapeutics, Inc.
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