Neurologically impaired mice improve after receiving human stem cells Wednesday, 04 June 2008 Scientists report a dramatic success in what may be the first documented rescue of a congenital brain disorder by transplantation of human neural stem cells into the brain of mice. The research, published by Cell Press in the June issue of the journal Cell Stem Cell, may lead the way to new strategies for treating certain hereditary and perinatal neurological disorders. This progress give hope to find a cure to a set of diseases in children with similar neurological condition that is invariably fatal. Nerve cell projections are ensheathed by a fatty substance called myelin that is produced by oligodendrocytes, a type non-nerve cell in the brain and spinal cord. Myelin enhances the speed and coordination of the electrical signals by which nerve cells communicate with one another. When myelin is missing or damaged, electrical signals are not properly transmitted. Previous studies have explored the potential utility of cell transplantation for restoring absent or lost myelination to diseased nerve fibers. Much of this research has made use of the “shiverer mouse” animal model which lacks normal myelin and typically dies within months of birth. Yet to date, no transplantation of human neural stem cells or of their derivatives, called glial progenitor cells, have ever altered the condition or fate of recipient animals. Dr. Steve Goldman and colleagues from the Departments of Neurology and Neurosurgery at the University of Rochester Medical Center, along with collaborators at Weill Medical College of Cornell University, NY, UCLA Medical Center, CA and Baylor University College of Medicine, TX, built on this earlier work by devising a more robust method for the acquisition and purification of human foetal glial progenitor cells. In addition, they developed a new cell delivery strategy, based on multiple injection sites, to encourage widespread and dense donor cell engraftment throughout the central nervous system of recipient mice. The researchers transplanted human glial stem cells into neonatal shiverer mice that also had a genetically deficient immune system. Immunodeficient mice were used to minimize the rejection of the transplanted cells. Dr. Steve Goldman and first author and scientist Martha Windrem have been working on shiverer mice for more than a decade. In work published in 2004 in Nature Medicine, the team restored myelin in a widespread area of an animal's brain, by injecting human stem cells that eventually become oligodendrocytes, the cells that produce myelin. In those earlier experiments, the team attempted to repair cells in only certain parts of the brain. Although the methods were effective, the treatment didn't actually improve the health of the mice. In the latest work, the team took advantage of the routes that cells commonly take to migrate from one region of the brain to another. They injected approximately 300,000 human stem cells into the brain of each mouse, choosing five particular spots because of their ability to serve as launch pads of sorts for stem cells to migrate and colonize the entire brain and spinal cord. The researchers found that the new transplant procedure resulted in infiltration of human glial progenitor cells throughout the brain and spinal cord. The engrafted mice exhibited robust, efficient and functional myelination. Most notably, many of the mice displayed progressive, neurological improvement and a fraction of the mice were actually rescued by the procedure. The work marks an important step toward the day when stem cells become an option for the treatment of neurological diseases in people. “The neurological recovery and survival of the mice receiving transplants was in sharp contrast to the fate of their untreated controls, which uniformly died by five months,” explains Dr. Goldman. Upon histological examination well over a year after the procedure, the white matter of the surviving mice had been essentially re-myelinated by human cells. “To our knowledge, these data represent the first outright rescue of a congenital hypo-myelinating disorder by means of stem or progenitor cell transplantation,” offers Dr. Goldman. The neuroscientists injected a type of foetal human stem cell known as glial stem cells into newborn mice born with a condition that normally claims their lives within about 20 weeks of birth, after a lifetime of seizures and other serious consequences. Not all of the transplanted mice fared well. Of 26 mice treated with stem cells, about three-quarters died, typically from seizures, within a couple of weeks of their untreated counterparts. But the six treated mice that lived longer recuperated to a degree hardly thought possible. The four mice that still survived one year after treatment improved rapidly, had no seizures, and were practically free of symptoms. The scientists plan to gather more evidence before trying the approach in sick children. In just two months, the glial stem cells multiplied and spread, covering nerve cells in almost the entire central nervous system, exactly mirroring their distribution in the brains of healthy mice. For several months after that, the cells produced myelin that coated nerve cells throughout the entire brain and spinal cord; from then on, the brain cells functioned normally, conducting impulses as quickly as in normal mice. "We kept expecting them to die. Not only did they not die, but they improved day by day," said Goldman, who is director of the Center for Translational Neuromedicine and professor of Neurosurgery and Neurology. “Although much work needs to be done to maximize the number of individuals that respond to transplantation, I think that these findings hold great promise for the potential of stem cell-based treatment in a wide range of hereditary and ischemic myelin disorders in both children and adults.” "It's extremely exciting to think about not only treating but actually curing a disease, particularly an awful disease that affects children," said Steven Goldman. "Unfortunately, right now, we can do little more for many of these conditions besides tell parents to prepare for their kids to die." Thousands of children with rare, fatal disorders known as paediatric leukodystrophies share a central problem with the shiverer mice: Their brain cells lack sufficient myelin, a vital fatty coating that wraps around cells in the brain like insulation around an electrical wire. Myelin coats long sections, known as axons, of brain cells called neurons, and without it, the electrical signalling between neurons becomes sluggish and muddied, causing a variety of symptoms. Myelin loss is at the heart of multiple sclerosis, and also plays a role in the symptoms of diabetes, high blood pressure, and other diseases. In children, diseases of myelin go by a host of names but share the same features: a childhood and young adulthood that may include weakness, difficulty standing or walking, seizures, dementia, paralysis, and ultimately, death. These diseases, which include Tay-Sachs, Krabbe's, Canavan's, Pelizaeus-Merzbacher, Vanishing White Matter Disease and a host of others are each rare, but collectively they kill thousands of children every year. Just last week, Lorenzo Odone, whose battle with one such disease, adrenoleukodystrophy, was featured in the film Lorenzo's Oil, passed away. Currently there is no treatment for any of these conditions. The stem cells established themselves and spread throughout the brain with similar success in all the transplanted mice, including the ones that died near the time of their untreated counterparts. So why did some mice live longer? Goldman believes it was a race against time: Many of the mice were so sick that constant seizures killed them before the stem cells could take hold, propagate, spread, and remyelinate brain cells. Reference: Neonatal Chimerization with Human Glial Progenitor Cells Can Both Remyelinate and Rescue the Otherwise Lethally Hypomyelinated Shiverer Mouse Martha S. Windrem, Steven J. Schanz, Min Guo, Guo-Feng Tian, Vaughn Washco, Nancy Stanwood, Matthew Rasband, Neeta S. Roy, Maiken Nedergaard, Leif A. Havton, Su Wang, and Steven A. Goldman Cell Stem Cell, Vol 2, 553-565, 05 June 2008 ......... ZenMaster
For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/ and http://www.geocities.com/giantfideli/index.html
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