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Permissive glia fail to excite scar response in CNS grafts
Newsdesk Permissive glia fail to excite scar response in CNS grafts into the host retina with distinct neuronal identity and appropriate neuronal projections”. They speculate
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Professor P Motta & D Palermo/SPL
What blocks most attempts at neuronal transplantation in the CNS? One possible culprit is glial scarring, and now research shows that prevention of glial scar formation might remove barriers to CNS transplants. “One of the greatest challenges for using neural transplantation to treat retinal or CNS diseases like Parkinson’s disease has been the poor survival and integration of transplanted neurons”, explains author Dong Feng Chen (Schepens Eye Institute, Harvard Medical School, Boston, MA, USA). His team and Swedish co-workers recently reported the result of retinal transplantation in mice lacking two constituents of the glial cytoskeleton—glial fibrillary acidic protein and vimentin. Strikingly, in the transgenic mice, transplanted cells moved within weeks into the host retina and formed apparently normal retinal neurons. In wild-type mice, neurons remained clustered around the injection site. Furthermore, the authors note, “transplanted cells integrated robustly
Glial cells to blame for neural transplant failure
that loss of the two proteins provides a permissive environment (in which reactive astrocytes and Müller cells lack intermediate filaments) for grafted neurons to migrate and extend neurites (Nat Neurosci 2003; 6: 863–68). Although glial scarring is not completely blocked in the transgenic mice, the central point, says Chen, “is that even by weakening the glial scar, it results in robust neural integration of
transplanted cells into the host neuronal environment”. Chen is optimistic that future agents that weaken or eliminate the glial barrier will allow neural graft integration, while Raymond Lund (Utah University Health Science Center, Salt Lake City, USA) is keen to emphasise that the research is a long way from successful human retinal transplantation. Chen admits, for instance, that “we need to know whether transplanted cells form functionally active connections with the host, and whether they restore visual function”. Lund points out that, in this study, the researchers “do no stain to show whether there are donor photoreceptors, nor do they use a recipient that has lost its photoreceptors.” And ultimately, the research does not explain “why quite a few investigators have managed to get similar integration in both retina and CNS structures without apparently manipulating the scar formation”. Kelly Morris
Neurons regenerate in absence of reactive astrocytes Mice that do not produce glial fibrillary acidic protein (GFAP) and vimentin show axon regeneration and functional recovery after hemisection of their spinal cords (Proc Natl Acad Sci USA 2003; 100: 8999–9004). This discovery offers the hope of new therapies for victims of severe spinal injury. GFAP and vimentin are structural proteins of the astrocyte cytoskeleton, and are upregulated in reactive astrocytes such as those involved in glial scarring at spinal-cord lesions. Not only do these cells act as physical barriers to axon growth, and therefore to the recovery of function, but they may also synthesise biochemical molecules that inhibit regeneration. “We thought that reducing reactive gliosis might help neurons regrow their axons and improve functional outcome by compensating the initial circuitry”, explains Minerva Gimenez y Ribotta (CSIC-Universidad Miguel Hernández,
Alicante, Spain). “So we used knockout mice for each, and for both, of these proteins”. The knockout mice underwent hemisection of the spinal cord, a procedure that causes complete dysfunction of the ipsilateral hindlimb. Over the following weeks, functionality of the hindlimbs was assessed by making the animals walk over grids, a test that demands that they not only move their feet but also do so very precisely if they are to avoid stumbling. “The mice with only one missing protein faired as poorly as the controls”, explains Gimenez y Ribotta, “but the double mutants showed a significant recovery of the lost function in the ipsilateral hindlimb within just 5 weeks, making far fewer footfalls”. By looking for nestin, a marker protein of astrocytes, the researchers found that astrocyte reactivity was much lower in the damaged cords of the double knockout mice than in those of the control or single knockout
THE LANCET Neurology Vol 2 September 2003
mice. Furthermore, in the doubleknockouts, reinnervation from descending supraspinal fibres was seen in the serotoninergic system. After only 3 weeks, numerous fibres had sprouted. Similarly, substantial numbers of fibres from the corticospinal tract were seen crossing from the intact to the damaged side of the cord. “Basically, these results show that by reducing astroglial reactivity we can permit axonal sprouting of the key descending systems required for walking”, says Gimenez y Ribotta. “Glial scars contain reactive astrocytes and activated microglia”, says Francisco Wandosell (Universidad Autónoma de Madrid, Spain), remarked. “Different insults might produce glial scars with different proportions of these cells, and different scars may have different responses. However, I feel this paper is moving us in the right direction.” Adrian Burton
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
523
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Professor P Motta & D Palermo/SPL
What blocks most attempts at neuronal transplantation in the CNS? One possible culprit is glial scarring, and now research shows that prevention of glial scar formation might remove barriers to CNS transplants. “One of the greatest challenges for using neural transplantation to treat retinal or CNS diseases like Parkinson’s disease has been the poor survival and integration of transplanted neurons”, explains author Dong Feng Chen (Schepens Eye Institute, Harvard Medical School, Boston, MA, USA). His team and Swedish co-workers recently reported the result of retinal transplantation in mice lacking two constituents of the glial cytoskeleton—glial fibrillary acidic protein and vimentin. Strikingly, in the transgenic mice, transplanted cells moved within weeks into the host retina and formed apparently normal retinal neurons. In wild-type mice, neurons remained clustered around the injection site. Furthermore, the authors note, “transplanted cells integrated robustly
Glial cells to blame for neural transplant failure
that loss of the two proteins provides a permissive environment (in which reactive astrocytes and Müller cells lack intermediate filaments) for grafted neurons to migrate and extend neurites (Nat Neurosci 2003; 6: 863–68). Although glial scarring is not completely blocked in the transgenic mice, the central point, says Chen, “is that even by weakening the glial scar, it results in robust neural integration of
transplanted cells into the host neuronal environment”. Chen is optimistic that future agents that weaken or eliminate the glial barrier will allow neural graft integration, while Raymond Lund (Utah University Health Science Center, Salt Lake City, USA) is keen to emphasise that the research is a long way from successful human retinal transplantation. Chen admits, for instance, that “we need to know whether transplanted cells form functionally active connections with the host, and whether they restore visual function”. Lund points out that, in this study, the researchers “do no stain to show whether there are donor photoreceptors, nor do they use a recipient that has lost its photoreceptors.” And ultimately, the research does not explain “why quite a few investigators have managed to get similar integration in both retina and CNS structures without apparently manipulating the scar formation”. Kelly Morris
Neurons regenerate in absence of reactive astrocytes Mice that do not produce glial fibrillary acidic protein (GFAP) and vimentin show axon regeneration and functional recovery after hemisection of their spinal cords (Proc Natl Acad Sci USA 2003; 100: 8999–9004). This discovery offers the hope of new therapies for victims of severe spinal injury. GFAP and vimentin are structural proteins of the astrocyte cytoskeleton, and are upregulated in reactive astrocytes such as those involved in glial scarring at spinal-cord lesions. Not only do these cells act as physical barriers to axon growth, and therefore to the recovery of function, but they may also synthesise biochemical molecules that inhibit regeneration. “We thought that reducing reactive gliosis might help neurons regrow their axons and improve functional outcome by compensating the initial circuitry”, explains Minerva Gimenez y Ribotta (CSIC-Universidad Miguel Hernández,
Alicante, Spain). “So we used knockout mice for each, and for both, of these proteins”. The knockout mice underwent hemisection of the spinal cord, a procedure that causes complete dysfunction of the ipsilateral hindlimb. Over the following weeks, functionality of the hindlimbs was assessed by making the animals walk over grids, a test that demands that they not only move their feet but also do so very precisely if they are to avoid stumbling. “The mice with only one missing protein faired as poorly as the controls”, explains Gimenez y Ribotta, “but the double mutants showed a significant recovery of the lost function in the ipsilateral hindlimb within just 5 weeks, making far fewer footfalls”. By looking for nestin, a marker protein of astrocytes, the researchers found that astrocyte reactivity was much lower in the damaged cords of the double knockout mice than in those of the control or single knockout
THE LANCET Neurology Vol 2 September 2003
mice. Furthermore, in the doubleknockouts, reinnervation from descending supraspinal fibres was seen in the serotoninergic system. After only 3 weeks, numerous fibres had sprouted. Similarly, substantial numbers of fibres from the corticospinal tract were seen crossing from the intact to the damaged side of the cord. “Basically, these results show that by reducing astroglial reactivity we can permit axonal sprouting of the key descending systems required for walking”, says Gimenez y Ribotta. “Glial scars contain reactive astrocytes and activated microglia”, says Francisco Wandosell (Universidad Autónoma de Madrid, Spain), remarked. “Different insults might produce glial scars with different proportions of these cells, and different scars may have different responses. However, I feel this paper is moving us in the right direction.” Adrian Burton
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
523