Scientists Learn How Stem Cell Implants Help Heal Traumatic Brain Injury

Scientists Learn How Stem Cell Implants Help Heal Traumatic Brain Injury  
Friday, 13 January 2012

For years, researchers seeking new therapies for traumatic brain injury have been tantalized by the results of animal experiments with stem cells. In numerous studies, stem cell implantation has substantially improved brain function in experimental animals with brain trauma. But just how these improvements occur has remained a mystery.

Now, an important part of this puzzle has been pieced together by researchers at the University of Texas Medical Branch at Galveston. In experiments with both laboratory rats and an apparatus that enabled them to simulate the impact of trauma on human neurons, they identified key molecular mechanisms by which implanted human neural stem cells — stem cells that are in the process of developing into neurons but have not yet taken their final form — aid recovery from traumatic axonal injury.

A significant component of traumatic brain injury, traumatic axonal injury involves damage to axons and dendrites, the filaments that extend out from the bodies of the neurons. The damage continues after the initial trauma, since the axons and dendrites respond to injury by withdrawing back to the bodies of the neurons.

"Axons and dendrites are the basis of neuron-to-neuron communication, and when they are lost, neuron function is lost," said UTMB professor Ping Wu, lead author of a paper on the research appearing in the Journal of Neurotrauma.

"In this study, we found that our stem cell transplantation both prevents further axonal injury and promotes axonal regrowth, through a number of previously unknown molecular mechanisms."

The UTMB researchers began their investigation with a clue from their previous work: they had determined that their neural stem cells secreted a substance called glial derived neurotropic factor, which seemed to help injured rat brains recover from injury. As a first step toward identifying the processes by which GDNF and neural stem cell transplantation produced their beneficial effects, Wu enlisted UTMB professors Larry Denner, Douglas Dewitt and Dr. Donald Prough to use proteomic techniques to compare injured rat brains with injured rat brains into which neural stem cells had been transplanted.

"We identified about 400 proteins that respond differently after injury and after grafting with neural stem cells," Wu said.

"When we grouped them using a state-of-the-art Internet database, we found that a group of cytoskeleton proteins was being changed, and in particular one called alpha-smooth muscle actin, which had never been reported in the neurons before."

Because so many of the proteins that changed were related to axonal structure and function, the UTMB scientists then focused on traumatic axonal injury. Initially working with rats, they confirmed that axons and dendrites suffered damage from trauma; implanted neural stem cells reduced this harm, as well as lowering levels of alpha-smooth muscle actin inside neurons that were raised after trauma.

To probe further into the molecular details of GDNF's role in reducing traumatic axonal injury, the researchers used a system in which human neurons were placed on a flexible membrane that was then suddenly distended with a precisely calibrated puff of gas. Their goal was to simulate the sudden compression and stretching forces exerted on brain cells by a blow to the head.

Initial results from this "rapid stretch injury model" matched those seen in rat experiments, with GDNF protecting axons and dendrites from additional damage in the period after trauma and significantly reducing alpha-smooth muscle actin levels boosted by the simulated injury. In addition, they found evidence linking alpha-smooth muscle actin with RhoA, a small protein that blocks axonal growth after injury. Finally, again taking a cue from their proteomic study, they turned their attention to one component of a protein known as calcineurin, finding that it interacted with GDNF to protect axons and dendrites in the RSI model.

"We're quite excited about these discoveries, because they're highly novel — we now know much more about how GDNF protects axons and dendrites from further injury and promotes their re-growth after trauma," Wu said.

"This kind of detailed study is essential to developing safe and effective therapies for traumatic brain injury."

Source: University of Texas Medical Branch at Galveston
Contact: Jim Kelly
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ZenMaster

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UW-Madison get NIH grant for ALS stem cell therapy

UW-Madison get $7.2M NIH grant for ALS stem cell therapy Friday, 21 September 2007 With the help of a $7.2 million grant from the National Institutes of Health (NIH), a team of University of Wisconsin-Madison researchers will explore the potential of stem cells and natural growth factors to treat amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. The grant, to be awarded over five years, will fund research aimed at finding novel therapies for treating a debilitating and nearly always fatal condition caused by the withering of motor neurons, the brain cells that control the body's muscles. "This is a great opportunity," says Clive Svendsen, who will direct the project along with UW-Madison neuroscientists Su-Chun Zhang and Gordon S. Mitchell. "There is a lot of synergy between our groups which provide for a lot of overlap that we think will help us get at some of the key issues of ALS." The grant will support a combined cell-based approach to treating ALS, an incurable disease with no proven effective treatments. An estimated 30,000 people in the United States suffer from ALS, and most patients die within three to five years of diagnosis. The new Wisconsin program will utilize both embryonic and foetal stem cells and will explore the possibility of stimulating healthy nerve cells to release growth factors and other chemicals to protect motor neurons. The work will focus on three strategies for promoting healthy motor neurons and hitching new and rescued motor neurons to the muscles they control. The tri-fold approach will be tested in concert in a rat model for ALS. Previous work at UW-Madison has shown that neural cells derived from foetal tissue and engineered to release a key growth factor known as GDNF, a chemical that promotes cell health, protected motor neurons in rats with ALS. However, the rescued nerve cells did not reattach to the muscles they control. Studies to be supported by the new NIH grant will look at transplanting cells engineered to release the GDNF growth factor in combination with motor neurons derived from embryonic stem cells. The hope is there may be some synergistic effect between the two types of cells that not only protect and augment motor neurons in the animal model, but also promote connections with muscles. Zhang, a professor of anatomy in the UW-Madison School of Medicine and Public Health, has previously successfully derived motor neurons from embryonic stem cells. "We're putting them right into the rat model and assessing their effects," explains Svendsen, a prominent stem cell researcher at UW-Madison's Waisman Center. "Motor neurons don't survive very well in transplants, and the hope is the cells in combination with GDNF release may promote a better result." In addition, studies with intriguing potential to address the failure of the respiratory system in ALS, the ultimate cause of death for patients with the disease, are also planned. Despite the fundamental importance of respiratory failure in ALS, it has been little studied. Work by Mitchell, a professor in the UW-Madison School of Veterinary Medicine, will explore the idea of using endogenous mechanisms in the body that seem to afford protection for motor neurons that control the respiratory system until the end stage of the disease. By inducing hypoxia, a condition where tissues are deprived of oxygen, the Wisconsin team hopes to prompt the release of growth factors that seem to have neuroprotective qualities on the respiratory motor neurons that drive the lungs. The new grant, according to Svendsen, is important because it directly addresses key unexplored issues on the frontier of regenerative medicine, an emerging field that seeks to regenerate and replace diseased or damaged tissues and cells. Adopted from a News Release from the UW-Madison. ......... ZenMaster

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Stem cell therapy rescues motor neurons in ALS model

Stem cell therapy rescues motor neurons in ALS model August 1, 2007

In a study that demonstrates the promise of cell-based therapies for diseases that have proved intractable to modern medicine, a team of scientists from the University of Wisconsin-Madison has shown it is possible to rescue the dying neurons characteristic of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disorder also known as Lou Gehrig's disease.

The new work, conducted in a rat model and reported today (July 31) in the online, open-access journal from the Public Library of Science, PLoS ONE, shows that stem cells engineered to secrete a key growth factor can protect the motor neurons that waste away as a result of ALS. An important caveat, however, is that while the motor neurons within the spinal cord are protected by the growth factor, their ability to maintain connections with the muscles they control was not observed.

"At the early stages of disease, we saw almost 100 percent protection of motor neurons," explains Clive Svendsen, a neuroscientist who, with colleague Masatoshi Suzuki, led the study at UW-Madison's Waisman Center.

"But when we looked at the function of these animals, we saw no improvement. The muscles aren't responding."

At present, there are no effective treatments for ALS, which afflicts roughly 40,000 people in the United States and which is almost always fatal within three to five years of diagnosis. Patients gradually experience progressive muscle weakness and paralysis as the motor neurons that control muscles are destroyed by the disease. The cause of ALS is unknown.

In the new Wisconsin study, nascent brain cells known as neural progenitor cells derived from human fetal tissue were engineered to secrete a chemical known as glial cell line derived neurotrophic factor (GDNF), an agent that has been shown to protect neurons but that is very difficult to deliver to specific regions of the brain. The engineered cells were then implanted in the spinal cords of rats afflicted with a form of ALS.

"GDNF has a very high affinity for motor neurons in the spinal cord," says Svendsen. When implanted, "the (GDNF secreting) cells survive beautifully. In 80 percent of the animals, we saw nice maturing transplants."

The implanted cells, in fact, demonstrated an affinity for the areas of the spinal cord where motor neurons were dying. According to Svendsen, the cells migrate to the area of damage where they "just sit and release GDNF."

The Wisconsin team transplanted the cells on one side of the spinal cord and used the untreated side to compare the affects of the transplanted cells and their chemical secretions.

"We only put the transplant in one small area of the spinal cord and only on one side," Suzuki says.

"The areas where we saw the human cells were the only areas where we saw protection of motor neurons."

But while the motor neurons exposed to GDNF were protected, the Wisconsin team was unable to detect the connections between the neurons and the muscles they govern.

"Even in animals that had lots of motor neurons surviving, we didn't see the (muscle) connection, which explained why we didn't see functional recovery," says Suzuki.

Although the obvious next step in the research is to try and ferret out the reasons the protected motor neurons are unable to hook up with muscles, Svendsen suggests the work further supports movement toward clinical trials in humans.

"We think the cells are safe, and they do increase the survival of the motor neurons," Svendsen argues.

"This may be very important for patients that lose neurons every day. However, it's not a trivial intervention - you have to drill a hole in the spinal cord to get the cells releasing GDNF in. But there are few options for these patients and we will continue to move forward with this approach." .........

ZenMaster

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For more on stem cells and cloning, go to CellNEWS at http://www.geocities.com/giantfideli/index.html

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