ChinaSCINet Update

[Wise Young]

Cielo,

khmorgan is right. I did not say that the doctors in Kunming were removing "scar" from the spinal cord. They were removing necrotic (dead) tissues and this was done within a week or two after spinal cord injury (not chronic). In fact, I have posted on a number of occasion to say that I strongly disagree with the use of the word "scar" in injured spinal cord and that there is no way of "removing scar" from injured spinal cords without causing more scar.

Wise.

[jsilver]

Originally Posted by Wise Young

Cielo,

khmorgan is right. I did not say that the doctors in Kunming were removing "scar" from the spinal cord. They were removing necrotic (dead) tissues and this was done within a week or two after spinal cord injury (not chronic). In fact, I have posted on a number of occasion to say that I strongly disagree with the use of the word "scar" in injured spinal cord and that there is no way of "removing scar" from injured spinal cords without causing more scar.

Wise.

I haven't posted for some time but I feel I must respond to Wise's claims with which I and many other SCI researchers fundamentally disagree. Also, what Wise just posted makes no sense. If he fundamentally disagrees with the word "scar" in the injured cord how can there be any cause for more "scar" if the structure does not exist. Whether one calls the glial barrier that develops over time in the injured cord scar or something else like "barrier" the continuing glial response following trauma is a huge problem in the chronically injured cord. if you wish to read a review that I wrote on the subject of glial scarring that is widely cited in the literature see "Regeneration beyond the glial scar" Nature Reviews, Feb. 2004, volume 5 pgs 146-156. Pay particular attention to figure 2 and the experiments associated with this figure which shows clearly the astroglial barrier which I and all others call "scar" that develops over time after SCI. This structure can become amazingly dense due to glial hypertrophy and adhesive junctions that form between the cells, without significant contributions from fibroblasts. Such scarring also expands greatly beyond the lesion deep into the white matter where axons and their ensheathing myelin have been lost and becomes quite physically obstructive to axon regeneration. The obstructive nature of the glial scar is demonstrated via a so-called micro-transplantation experiment. The good news is that there are places even in the chronically injured spinal cord beyond the glial scar directly at the lesion where axonal growth is still possible. I suggest any who are interested to read this and then ponder its significance in relation to Wise's claims of no such thing as glial scarring as well as his hope for regeneration at chronic stages without dealing with this problem. In attempts to promote regeneration at chronic stages following injury this scar structure especially at the primary lesion site needs to be surgically removed or broken down or overcome via a variety of strategies if axons are to get through. Once removed there are techniques that can be used to minimize the re-appearance of scar.

[khmorgan]

Never mind...

[havok]

I am curious how regeneration using UBCMC is suppose to bypass the lesion. Is it able to grow through it?

[Barrington314mx]

Originally Posted by khmorgan

Never mind...

why did you edit that? i thought what you had said made sense.

[Wise Young]

Originally Posted by havok

I am curious how regeneration using UBCMC is suppose to bypass the lesion. Is it able to grow through it?

Havok,

It seems that Jerry Silver and I have disagreements on more than just terminology. In previous discussions, I objected to use of the word scar to characterize astroglial proliferation at the edges of the injury site in the spinal cord. To me, scar means a tough collagenous tissue formed by fibroblasts in skin and other tissues that have been cut or otherwise damaged.

We all know and have one or more scars on our skin. When one cuts the spinal cord, fibroblasts from surrounding tissues invade into the spinal cord. The spinal cord regards these fibroblasts as outsiders and astrocytes proliferate around them to form what I agree is a true scar. Most scientists who work on spinal cord injury models where the spinal cord is cut often talk about scars in the spinal cord.

A large majority of people with spinal cord injury do not have penetrating wounds of the spinal cord injury in which fibroblasts have invaded. They have had compression or contusion (rapid indentation) of the spinal cord. Usually, no or only a few fibroblasts invade into the injury site of spinal cords that have been injured by compression or contusion. Astrocytes do proliferate at the edges of the injury site. I don't think that astrocytic proliferation should be called "scar". Jerry thinks the name is appropriate.

I had thought that my disagreement with Jerry was largely symantic. However, his post here suggests otherwise. In 1997, the MASCIS (multicenter animal spinal cord injury study) published a paper describing the histological appearance of the contusion site of over 500 spinal-injured rats, showing many axons growing into the injury site despite astrocytic proliferation around the injury site. I attach a copy of the paper here. Our work suggests that axons can and will grow into the contusion site, despite the presence of glial cells around the injury site.

Many other studies have now shown that axons will grow through so-called "glial scars" without having to remove the scars surgically or otherwise. The clearest example of this is the recent work of Liu, et al. (2010) showing that knocking out a single gene (PTEN) will result in regrowth of the corticospinal tract in mice. They did nothing to remove the "glial scar" in the spinal cord.

Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, Tedeschi A, Park KK, Jin D, Cai B, Xu B, Connolly L, Steward O, Zheng B and He Z (2010). PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci 13: 1075-81. F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA. Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.

So, in answer to your question, yes, we are hoping that the umbilical cord blood transplant and lithium treatment will facilitate axon growth across the injury site.

Wise.

[khmorgan]

Originally Posted by Barrington314mx

why did you edit that? i thought what you had said made sense.

Sorry, I decided that I did not want to stir the pot of controversy over the definition of a four letter word any more, even if I agree with both sides.

[jsilver]

Originally Posted by Wise Young

Havok,

It seems that Jerry Silver and I have disagreements on more than just terminology. In previous discussions, I objected to use of the word scar to characterize astroglial proliferation at the edges of the injury site in the spinal cord. To me, scar means a tough collagenous tissue formed by fibroblasts in skin and other tissues that have been cut or otherwise damaged.

We all know and have one or more scars on our skin. When one cuts the spinal cord, fibroblasts from surrounding tissues invade into the spinal cord. The spinal cord regards these fibroblasts as outsiders and astrocytes proliferate around them to form what I agree is a true scar. Most scientists who work on spinal cord injury models where the spinal cord is cut often talk about scars in the spinal cord.

A large majority of people with spinal cord injury do not have penetrating wounds of the spinal cord injury in which fibroblasts have invaded. They have had compression or contusion (rapid indentation) of the spinal cord. Usually, no or only a few fibroblasts invade into the injury site of spinal cords that have been injured by compression or contusion. Astrocytes do proliferate at the edges of the injury site. I don't think that astrocytic proliferation should be called "scar". Jerry thinks the name is appropriate.

I had thought that my disagreement with Jerry was largely symantic. However, his post here suggests otherwise. In 1997, the MASCIS (multicenter animal spinal cord injury study) published a paper describing the histological appearance of the contusion site of over 500 spinal-injured rats, showing many axons growing into the injury site despite astrocytic proliferation around the injury site. I attach a copy of the paper here. Our work suggests that axons can and will grow into the contusion site, despite the presence of glial cells around the injury site.

Many other studies have now shown that axons will grow through so-called "glial scars" without having to remove the scars surgically or otherwise. The clearest example of this is the recent work of Liu, et al. (2010) showing that knocking out a single gene (PTEN) will result in regrowth of the corticospinal tract in mice. They did nothing to remove the "glial scar" in the spinal cord.



So, in answer to your question, yes, we are hoping that the umbilical cord blood transplant and lithium treatment will facilitate axon growth across the injury site.

Wise.

Glial scarring is far more than simply glial cell proliferation. Did I not make myself perfectly clear? If not, then I reiterate. Glial scarring is comprised of astroglial HYPERTROPHY with adherens junctions forming between the cells which, over time, can completely take over all remaining space once axonal and myelin debris are removed. The scar forms a tenacious membrane which becomes tougher over time and we know this first hand in my lab because we are trying to deal with it in our chronic regeneration studies. The scar SURROUNDS the core of the lesion which has lots of other cell types including inflammatory cells, resident stem cells (NG2 giia), pericytes, ependymal cells, and relatively more or fewer fibroblasts depending on whether the lesion penetrates the dura. There is new evidence emerging that meningeal fibroblasts can also invade contusive injury lesion cores and these cells produce their own cadre of inhibitory molecules. Over time the cells in the lesion core change in numbers and types and sometimes Schwann cells also invade the lesion core. Why and how Schwann cells do this is unknown but when they do they can attract axons (mostly sensory axons from the roots) into the lesion core where they do nothing productive except swirl around within the walls of the scar. Everything in biology is a balance, nothing is absolute, so there are ways to overcome the axon growth inhibiting properties of the scar. Schwann cells provide powerful substrates for axon growth so they can overcome scar if they form a continuous pathway through the scar wall. It has been shown that neurotrophins when expressed just outside an established scar can attract some sensory axons of the dorsal columns through an established scar wall. The PTEN observation you keep making is not valid because these experiments are done at acute stages after injury with PTEN deletion occurring long before injury. So the scar has not yet developed and axons actually use astrocytes as a substrate to cross the injury. The PTEN experiments are mostly done in mice where the lesion scar following surgical cutting or forceps crushing is relatively small compared to that which develops after similar manipulations in rat or other larger mammals. But even in the mouse, with a narrow lesion, and even when axons are being driven strongly by PTEN deletion the great majority of regenerating axons still get hung up at the scar. In the future we shall see if PTEN deletion of particular neuronal populations in the adult can allow for some axons to penetrate an already established scar but my bet is that their numbers will be few and the robustness of regeneration compared to that at acute injury will be greatly diminished. I believe that at chronic stages we will need to build a robust bridge across the lesion for any hope of fostering significant long distance regeneration. When you raise the hope that lithium plus umbilical cord cells, neither of which have been convincingly shown to provide for long distance regeneration even at acute stages, will somehow allow axon regeneration through established scar without further manipulation or bridge building attempts, you are sorely under estimating the myriad of obstacles that develop over time in the injured cord not only from the glia but also from the axons that have become dystrophic and locked in place. I see no evidence in the published literature that lithium even comes close to the potency of the effects of long term genetic or ShRNA deletion of the PTEN gene. Clearly there is no evidence that stem cells of any type can foster regeneration at long chronic stages. If your patients get better, and I hope they do, the anatomical substrate for recovery will highly likely not be via regeneration through the glial scar.

[Tufelhunden]

Dear Drs. Young and Silver,

I wanted to thank you both for your participation in this forum. I regularly attend seminars as part of my educational requirement for my PhD in economics, where scholars engage themselves in constructive debate.

From a scholarly perspective, I appreciate this very much. In economics, during seminar presentations of working papers is definitely where the rubber meets the pavement and experiencing you giants of your field interact first hand is beneficial to all here.

[lakboy]

Hello Jsilver and the doc, Both of u seem to have disagreements on what happens to the cord that has been injured for a long time, that is fair , I have questions to both of you, you are first , have you started a trial that atleast that addresses a chronic spinal cord injury ? I do not think so , and I agree with you that Lithium is a bit iffy , I tried it and it did not work for me, so on that account you are probably right, but jsilver , all the SCI community wants is hope an that some one out there is action. Wise doing some thing about it , and for me that is much more important than always citing examples as to why this or that does not happen , we are too used to hearing the words that say , it can't happen , IT WILL,