Neurons regenerate in absence of reactive astrocytes

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THE LANCET Neurology Vol 2 September 2003 http://neurology.thelancet.com 523

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What blocks most attempts at neuronaltransplantation in the CNS? Onepossible culprit is glial scarring, andnow research shows that preventionof glial scar formation mightremove barriers to CNS transplants.“One of the greatest challenges for usingneural transplantation to treat retinal orCNS diseases like Parkinson’s diseasehas been the poor survival andintegration of transplanted neurons”,explains author Dong Feng Chen(Schepens Eye Institute, HarvardMedical School, Boston, MA, USA). Histeam and Swedish co-workers recentlyreported the result of retinal transplant-ation in mice lacking two constituentsof the glial cytoskeleton—glial fibrillaryacidic protein and vimentin.

Strikingly, in the transgenic mice,transplanted cells moved within weeksinto the host retina and formedapparently normal retinal neurons. Inwild-type mice, neurons remainedclustered around the injection site.Furthermore, the authors note,“transplanted cells integrated robustly

into the host retina with distinctneuronal identity and appropriateneuronal projections”. They speculate

that loss of the two proteins provides apermissive environment (in whichreactive astrocytes and Müller cells lackintermediate filaments) for graftedneurons to migrate and extend neurites(Nat Neurosci 2003; 6: 863–68).

Although glial scarring is notcompletely blocked in the transgenicmice, the central point, says Chen, “isthat even by weakening the glial scar, itresults in robust neural integration of

transplanted cells into the hostneuronal environment”. Chen isoptimistic that future agents thatweaken or eliminate the glial barrier willallow neural graft integration, whileRaymond Lund (Utah UniversityHealth Science Center, Salt Lake City,USA) is keen to emphasise that theresearch is a long way from successfulhuman retinal transplantation.

Chen admits, for instance, that “weneed to know whether transplantedcells form functionally activeconnections with the host, and whetherthey restore visual function”. Lundpoints out that, in this study, theresearchers “do no stain to showwhether there are donorphotoreceptors, nor do they use arecipient that has lost itsphotoreceptors.” And ultimately, theresearch does not explain “why quite afew investigators have managed to getsimilar integration in both retina andCNS structures without apparentlymanipulating the scar formation”.Kelly Morris

Permissive glia fail to excite scar response in CNS grafts

Mice that do not produce glialfibrillary acidic protein (GFAP) andvimentin show axon regeneration andfunctional recovery after hemisectionof their spinal cords (Proc Natl AcadSci USA 2003; 100: 8999–9004). Thisdiscovery offers the hope of newtherapies for victims of severe spinalinjury.

GFAP and vimentin are structuralproteins of the astrocyte cytoskeleton,and are upregulated in reactiveastrocytes such as those involved inglial scarring at spinal-cord lesions.Not only do these cells act as physicalbarriers to axon growth, andtherefore to the recovery of function,but they may also synthesisebiochemical molecules that inhibitregeneration.

“We thought that reducing reactivegliosis might help neurons regrow theiraxons and improve functional outcomeby compensating the initial circuitry”,explains Minerva Gimenez y Ribotta(CSIC-Universidad Miguel Hernández,

Alicante, Spain). “So we used knockoutmice for each, and for both, of theseproteins”.

The knockout mice underwenthemisection of the spinal cord, aprocedure that causes completedysfunction of the ipsilateral hindlimb.Over the following weeks, functionalityof the hindlimbs was assessed bymaking the animals walk over grids, atest that demands that they not onlymove their feet but also do so veryprecisely if they are to avoid stumbling.

“The mice with only one missingprotein faired as poorly as thecontrols”, explains Gimenez y Ribotta,“but the double mutants showed asignificant recovery of the lost functionin the ipsilateral hindlimb within just5 weeks, making far fewer footfalls”.

By looking for nestin, a markerprotein of astrocytes, the researchersfound that astrocyte reactivity wasmuch lower in the damaged cords ofthe double knockout mice than inthose of the control or single knockout

mice. Furthermore, in the double-knockouts, reinnervation fromdescending supraspinal fibres was seenin the serotoninergic system. After only3 weeks, numerous fibres hadsprouted. Similarly, substantialnumbers of fibres from thecorticospinal tract were seen crossingfrom the intact to the damaged side ofthe cord.

“Basically, these results show thatby reducing astroglial reactivity we canpermit axonal sprouting of the keydescending systems required forwalking”, says Gimenez y Ribotta.

“Glial scars contain reactiveastrocytes and activated microglia”,says Francisco Wandosell(Universidad Autónoma de Madrid,Spain), remarked. “Different insultsmight produce glial scars withdifferent proportions of these cells,and different scars may have differentresponses. However, I feel this paper ismoving us in the right direction.”Adrian Burton

Neurons regenerate in absence of reactive astrocytes

Glial cells to blame for neural transplant failure

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