Sunday, 3 April 2016

Astrocytic scar is good for you

Anderson MA, Burda JE, Ren Y, Ao Y, O'Shea TM, Kawaguchi R, Coppola G, Khakh BS, Deming TJ, Sofroniew MV. Astrocyte scar formation aids central nervous system axon regeneration. Nature. 2016. doi: 10.1038/nature17623. [Epub ahead of print]

Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration.



The dogma in MS research is that the astrocytic scar limited remyelination and oligodendrocyte migration in order to repair. In this study they suggest that the dogma is that the astrocytic scar prevented nerve regeneration but in the conturary the scar helps the regeneration. They do this three ways which increasingly seems to be the high-impact research norm, in that you do the same experiment three of four differnt ways. I suppose this gives you more confidence in the result is real but it must be said it does not seem very compatibilte with the idea of the 3Rs of animal reseserach which is part of EU law. The 3Rs are reeding, rightin and rithmatic. OK that is not the case..... it is refinement (do your experiments in a more informative way), reduction (use fewer animals) and replacement (don't use animals), but it seems the editors and reviewers of the journals, mainly American, don't give a stuff about 3Rs and are demanding that you do the same experiment 3 different ways.



The work is not in MS, but experimental spinal cord injury(SCI). Astrocyte scar formation is complete by two weeks after SCI in adult mice and is critically dependent on astrocyte proliferation. This is known as gliosis.



To prevent astrocyte scar formation, they used two  transgenic loss-of-function mouse models that (1) kills proliferating scar-forming astrocytes via astrocyte-specific expression of gene (thymidine kinase) that makes cells susceptible killing by an antibiotic (e.g. gancyclovir (2) Discrupts astrocyte function by blocking a  growth factor for astrocyte growth. They also got rid of pre-formed scars by (3) making the astrocytes susceptible to a toxin. 

They then used nerve grow factors to stimulate nerve regrowth and if they blocked the scar forming then they got more sprouting of nerves


However, this causes an intellectual problem as it has been reported that blockage of the scar is good for lesional damage. This study therefore contrasts with the views of others

Mayo L, Trauger SA, Blain M, Nadeau M, Patel B, Alvarez JI, Mascanfroni ID, Yeste A, Kivis√§kk P, Kallas K, Ellezam B, Bakshi R, Prat A, Antel JP, Weiner HL, Quintana FJ. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med. 2014; 20(10):1147-56. 

Studies are now been supported to look at blocking astrocytes for the generation of CNS autoimmunity. Is it going to be a disaster zone? 

We won't know until it is done, but maybe we need to get to the bottom of this before doing the humans studies. 

It is surprsing that killing off astrocytes were not associated with lots of problems, especially as they are supposed to make the blood brain barrier impermeable and when you look in spinal cord injury certainly in humans then some of the problems worsen with time. Is this because new nerve sprouts grow causing pain and spasticity or is it that nerves are still dying? I suspect it is a bit of both as it is known that there is nerve plasticity after damage.

However, it highlights a biological problem in that the same molecule or cells can do two or more opposing effects. Therefore, if you are blinkered and do not think of the biology of the problem as a whole then sometimes you get problems (e.g. there are pathogenic B cells and regulatory B cells deplete all of them maybe you can suffer the consequences of lack of B cell regulation.eg.may be a relapse) Likewise astrocytes have many functions such as controling the neural support factors. 

In EAE there are lots of astrocytic scars in progresive disease and the nerves in them don't look too healthy, should we get rid of the scars?  However, is this the secret of demyelination that the astrocytic scar is helping keeping the demyelinated axons alive, the scar is a repair feature after all. Astrocytes have been neglected for too long maybe this is about to change

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