STEM CELL TRANSPLANTS IN ANIMALS HOLD PROMISE FOR HELPING HUMANS WITH NEUROLOGICAL WOES

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STEM CELL TRANSPLANTS IN ANIMALS HOLD PROMISE FOR HELPING HUMANS WITH NEUROLOGICAL WOES.

ORLANDO, Tuesday, Nov. 5 - The treatment of ailments with transplant strategies that replace lost or damaged cells in the nervous system with a healthy crop is getting a push forward thanks to new findings on stem cells.

Once worked out, transplants could potentially restore function in large numbers of people afflicted with neurological problems, such as spinal cord injury, stroke, brain trauma, Parkinson's disease, Alzheimer's disease, Huntington's disease and Lou Gehrig's disease. New research on stem cells was reported today during the 32nd annual meeting of the Society for Neuroscience.

In the past, researchers have had some success with experimental transplant techniques that use malleable cells from embryos, but acquiring sufficient amounts for the procedures is difficult. Stem cells have special traits that could solve this problem. Researchers can derive the cells from embryos as well as other tissues in the lab and mass produce them to create huge stock piles. Stem cells also can turn into different types of cells in the nervous system, according to studies. Now new research in animals provides additional evidence that these cells are ideal for transplant procedures. Batches of the cells transform into specific cell types, integrate into the nervous system and, in one of the studies, reinstate lost functions.

In the study that tested function, researchers transplanted human stem cells into rats that had damage to their nerve cells from a spinal cord injury.

Nerve cells transfer signals back and forth between the brain and spinal cord to the rest of the body. Once injured, however, unlike many other body components, cells in the adult spinal cord and brain cannot adequately repair themselves. Communication becomes permanently impaired and problems erupt. For some 250,000 Americans with spinal cord injuries this typically means permanent paralysis, the inability to move or a loss of sensation.

"There is no clinically feasible cure or even effective treatment for reversing the dysfunction that occurs following a spinal cord injury," says Evan Snyder, MD, PhD, of Harvard Medical School. "Our research suggests that transplants of stem cells, including those from human origin, can yield nerve cells that become integrated into the brain and spinal cord circuitry and offer recovery of lost function in the legs."

In the first part of the study, the researchers gave adult rats a moderate spinal cord injury. Then one to four weeks later, Snyder and his colleagues injected a transplant of stem cells into the fluid-filled cavity that forms after a spinal injury, known as a syrinx. As a control another group of injured rats received a fake transplant consisting of tissue or tissue culture fluid without stem cells. The batch of stem cells used in the experiment originated from the brains of human fetal cadavers.

An analysis of the transplanted stem cells indicates that they transformed into nerve cells and glia, cells that support and insulate nerve cells. Evidence also shows that some of the stem cell-derived nerve cells produced the molecule choline acetyltransferase. This indicates that they transformed into a special type of nerve cell, termed a motor neuron, which resides in the spinal cord and specifically aids movement.

The researchers also conducted dye tests to trace the pathways of the cells. "The results indicate that some nerve cells grew processes that extended below the transplant site towards the lower part of the spinal cord and above the transplant site towards the brain, as far as the thalamus brain region, which helps with sensation and movement," says Snyder. "This suggests that the transplanted cells can integrate into the neural circuitry."

In a final part of the study, the researchers tested whether the cells actually function and improve movement. Studies that tested cell signaling indicate that in response to touch and movement-related tasks, rats with transplants have improved cellular activity in the cortex brain areas, which carry out complex movement actions. Also rats with transplants performed better on tasks that tested their ability to walk in a coordinated fashion as well as tasks that tested their ability to support their bodies with their back legs.

"The results may indicate that stem cell transplants to the injured spinal cord can integrate and improve functions directed from brain centers that carry out complex actions," says Snyder.

As a next step the researchers plan to further examine the cell signaling from the transplants and determine if the results are long-lasting and how much of the improvement is mediated by the transplanted cells as opposed to recovery induced in the animals' own nerve connections by virtue of the stem cell transplant.

Another study on animals also indicates that transplants of cells derived from bone marrow could help repair damage from spinal cord injury.

So far, much of the research on stem cells has focused on lines that are derived from embryos. These cells seem particularly malleable and adept at transforming into various types of cells found in the nervous system. Since there are ethical issues surrounding the use of these cells, however, researchers are also examining the ability of stem cells from other tissues to help repair spinal cord and brain damage.

"Stem cells from bone marrow are readily obtainable from procedures that are already common practice in human medicine," says Mark Tuszynski, MD, PhD, of the University of California in San Diego. "We have found that transplantation of these cells in combination with genetic techniques may work just as well as other types of stem cell transplants in inducing the damaged spinal cord to regrow its circuitry."

In the study, Tuszynski and his colleagues made batches of cells for transplants by taking stem cells from the bone marrow of adult rats and adding chemical factors that induced them to become neural cells. They genetically modified some of the cells to make them secrete brain-derived neurotrophic factor, a molecule that is known to nourish the growth of nerve cells. Then they injected the genetically-modified bone marrow cells into eight rats at the site of a spinal cord injury. Another group of eight injured rats received transplants of bone marrow cells that were not genetically altered. Lastly, four injured rats received no implants as a control.

The researchers waited three months and then examined the sites of transplantation. "While the unaltered bone marrow stem cells showed signs that their processes grew and slightly penetrated the injured site, the genetically-modified cells showed extensive penetration," says Tuszynski. Rats that received no implants showed no effect.

"The results suggest that the stem cell transplants, particularly the genetically modified batch, can grow and repair damaged circuitry," says Tuszynski. "In the future this approach could represent a clinically practical method to repair damage in spinal cord injured patients."

As a next step the researchers plan to test whether the transplants help the animals regain lost movement abilities.

Another group of researchers finds evidence in animals that stem cell transplants also can transform into specialized functioning nerve cells in the brain.

"Previous studies have shown that stem cells undergo some changes once they are implanted into the brain that make them resemble nerve cells," says Anders Björklund, MD, of Lund University in Sweden. "In the present study we have for the first time been able to clearly demonstrate that transplanted stem cells can develop into fully functional brain cells that are specific to the region where they are implanted."

In the study, the researchers used a stem cell line derived from the brains of embryo rats. They injected the stem cells into the brains of newborn rats. Specifically the cells were injected into the outer layer of the brain, known as the cortex, which controls many complex functions, and an inner brain region, the hippocampus, known for its ability to aid memory. Then, 3 to 16 weeks later the researchers examined the transplant regions. "The implanted cells showed signs that they developed into very specialized nerve cells found in these regions, termed pyramidal nerve cells, because of their pyramid shape," says Björklund.

Additional research that traced the cells' connections and electrical activity also indicates that they integrated into the brain's circuitry. The cells developed processes that extended and made appropriate connections with other cells and showed the electrical properties of fully mature cortical pyramidal nerve cells. Furthermore results indicate that they could receive and send messages.

"Together the findings indicate that stem cell transplants in the brain develop physiological properties of specialized mature nerve cells that become functionally integrated into the existing circuitry," says Björklund. "Given time and effort, stem cell technology holds promise to turn cell therapy from a highly experimental procedure into a clinically useful treatment for large numbers of patients with hitherto intractable neurodegenerative diseases."

To get closer to this goal, Björklund next plans to test the transplants in animals with neurodegenerative diseases.