What happens to the glial scar?

dr_bubo · 09-23-2003, 01:35 AM

Dear Wise,

When Lima or Huang is doing their surgery, do they remove or change the glial scar?
if yes, what they do, if not, what do you think will happen to it when the OEG cells start to act?
Thanks
Bubo

Wise Young · 09-24-2003, 08:42 AM

Bubo, if you read the descriptions of the procedures, you will find that neither Dr. Huang nor Dr. Lima removes the "glial scar". None of the animal studies that implanted OEG into the spinal cord did anything about glial scars. I personally am not convinced that glial scars provide a mechanical obstacle to axonal regeneration in the spinal cord. Even if the scars were important, there is nothing much that we can do about it. To my knowledge, there is no treatment that has been successful in preventing glial scars other than cell transplants (including OEG) which have been reported to reduce glial scar formation.

Wise.

Max · 09-24-2003, 09:48 AM

Quote:

Originally posted by Wise Young:

Bubo, if you read the descriptions of the procedures, you will find that neither Dr. Huang nor Dr. Lima removes the "glial scar". None of the animal studies that implanted OEG into the spinal cord did anything about glial scars. I personally am not convinced that glial scars provide a mechanical obstacle to axonal regeneration in the spinal cord. Even if the scars were important, there is nothing much that we can do about it. To my knowledge, there is no treatment that has been successful in preventing glial scars other than cell transplants (including OEG) which have been reported to reduce glial scar formation.

Wise.

Wise,
Why can't glial scars be removed with laser?

dr_bubo · 09-27-2003, 05:19 AM

[ if the scars were important, there is nothing much that we can do about it.

Wise,
Why can't glial scars be removed with laser?[/QUOTE]

I heard that there is a chondro..something ABC which removes the scar... was it ever tested on human? if it does, anyone plan to try it before planting OEG and compare the results without this enzyme?
Bubo

EAA · 09-27-2003, 08:30 AM

I understand that Dr. Lima does remove a small amount of glial scar at the two ends of the injury. He does not try to remove all the scar but he does cut in an opening for the new cells.

George78 · 09-27-2003, 09:05 AM

New hope for the paralysed as scientists re-grow spinal cords (Filed: London Telegraph 13/07/2003)

Thirty years of research culminate in a 'Eureka!' moment for a French biologist working to regenerate severed nerve endings, reports Kim Willsher in Paris.

French scientists have discovered a way to regenerate damaged spinal cords in a breakthrough that might eventually allow paralysed people to walk again.

They have succeeded in regrowing the broken spinal cords of mice after identifying and eliminating two proteins that create scar tissue. This had prevented nerve endings from repairing themselves.

When the scientists, from the French National Health and Medical research institute, manipulated the genes of the mice so that they did not produce these proteins, they discovered that the spinal cord regrew within weeks, enabling the animals to run around again.

Until now the regeneration of nerve cells - or neurones - in the brain and the spinal column has been considered impossible. Previous attempts to restore locomotion by connecting the two extremities of a severed spine have always failed. The research team is now working on ways of using the discovery to develop a treatment for humans.

Prof Alain Privat, 59, who led the team of biologists from the Languedoc University of Science in Montpellier, in the south of France, told The Telegraph yesterday: "It's a very important breakthrough because for the past 100 years researchers working on the regeneration of the central nervous system have been unable to crack this problem. Nobody envisaged being able to repair the system because for a very long time they thought it was something inherent to the fibres themselves that meant they couldn't grow back and restore movement.

"Today, after six years of research, we are sure that we can make them work again if we can stop these two proteins from being produced."

The team is now working on adapting the process so that it can be applied first to mice and monkeys whose genes have not been modified, before carrying out tests on human patients. The key will be to find ways to inhibit the two proteins that stop the cord from repairing itself.

"We've proved that it is possible, but it's going to take at least five years to find out if the technique can be applied to humans. We can produce mutant mice but not mutant people, so we have to find other ways of tackling these proteins," said Prof Privat.

"I cannot be 100 per cent sure it will work on humans but I think the chances are very reasonable. It should work but until we do it we won't be sure."

The next stage involves developing a "genetic treatment" that could be applied to a damaged spine to halt the scarring process and stimulate the regrowth of the nerves. The researchers are also looking at whether the regeneration of the neurones can be jump-started in older injuries, enabling paralysed people such as Christopher Reeve, the actor, to benefit.

Prof Privat believes that the technique could also be used to treat brain injuries and degenerative conditions such as Parkinson's disease. "The neurons in the brain are very similar to those in the spinal cord," he said.

The professor, who is the director of the national health and medical research institute at Languedoc University, has worked with a team of three researchers to try to crack the secret of repairing spinal cord neurones.

The team identified two key proteins, Vimentine and Glial Fibrillary Acidic Protein (GFAP). These proteins, they discovered, were produced in large quantities after a spinal injury and formed a scar, described as an impenetrable wire fence, around the damaged nerve endings, preventing messages being transmitted to the brain.

Under his guidance, his researchers took 100 ordinary laboratory mice and divided them into four groups. The first was left alone as a control set, the second and third were genetically altered to eliminate one of the proteins, and the last group was "double mutants", lacking the genes that produced both proteins. The mice were all tested for their ability to run on a treadmill before their spines were cut.

Prof Privat, 59, said: "After two or three weeks there was a small group of animals that was performing better than the others. After four weeks they were moving their back legs and most of their motor function appeared to have been restored.

"We discovered that the control group and those whose genes had been only partially manipulated remained permanently paralysed. However, the mice in which both the proteins had been knocked out had recovered the use of their legs.

"When we examined these mice we found that there were no scars on the spinal cord fibres, the nervous system circuitry had been reconstructed and that after four weeks there was almost no remnants of paralysis in their hind legs.

"Thanks to this genetic modification the scarring that seems to be the cause of the paralysis didn't happen and the nerve fibres were able to grow back.

"He recalled the moment he and his team realised that they had achieved the breakthrough. "It took just a few seconds for us to realise that we had finally done it."It was a real 'Eureka!' moment and I jumped into my office where I had a very old bottle of my favourite Scotch, Glenlivet. I said to the others, "This is the time to crack it open'," Prof Privat added.

"It is absolutely ground-breaking. I started working on this subject around 30 years ago and I had finally done it."

One of the first problems he faces, however, is finding the estimated £3.5 million ( *5 million) needed to continue the research. Until now, the Montpellier team, hit by French government budget cuts, has relied on cash from private associations dedicated to those paralysed by spinal injuries. He said: "We need a relatively small sum of money. We have these encouraging results but barely the means to go on."

The results of the team's research will be published by the National Academy of Sciences, based in Washington, this month.

Wise Young · 09-27-2003, 10:09 AM

Max,

Let me try to answer the question: Why can't lasers be used to remove the "scar"?

1. There is no "scar" in the traditional sense of the word in most injured spinal cords. Scar usually means a fibrous tissue made by fibroblasts. In most closed spinal cord injuries, where there is no penetrating wound, what one gets is a proliferation of glial cells at the edges of the injury site. While some scientists have called this a "scar". I disagree with them and don't think that they should use the word scar for glial proliferation. When there is a penetrating wound of the spinal, however, fibroblasts do invade into the spinal cord. The central nervous system will wall off what they consider to be "peripheral" tissues. It does so by having glia proliferate at the borders of wounds, where they eventually form the CNS side of the peripheral/central interface. Glial cells proliferate around cells that they consider to be "outside" of the central nervous system, including, for example Schwann cells. On their side (i.e. the peripheral side), fibroblasts and other cells lay down a thin layer of extracellular matrix that is called the basal lamina. Axons like to grow on basal lamina rather than through them. Also, as Jerry Silver has discovered, proliferating glial cells secrete a substance called chondroitin-6-sulfate proteoglycan (CSPG) and CSPG is known to inhibit axonal growth; chondroitinase is an enzyme that breaks down CSPG and is known to encourage regeneration in cut spinal cord injury (which by the way, is a penetrating wound). Please, I am trying my best to explain this situation so that people do not make the simplistic assumption that a "glial scar" prevents regeneration and that all that one has to do is cut out the "scar".

2. Lasers cannot (at least available ones) do not discriminate between different kinds of cells. CO2 lasers (the most common surgical variety) act by heating up water inside cells and killing them. If you have ever used a laser, you will understand that they are not particularly good as a surgical tool. They kill a lot of cells all around (bystander injury) them due to the heat and they also do not penetrate very deeply.

3. Part of the function of the OEG cells is to provide a permissive environment for axonal growth through the injury site and surrounding spinal cord. The neurosurgeon who is working with Dr. Lima is not "removing" scar when he does a midline myelotomy (cutting along the midline of the spinal cord to minimize cutting across axons). They are just making an opening in the spinal cord so that they can place the nasal mucosa. Dr. Huang avoids touching the injury site altogether. He is injecting the OEG cells into the cord and animal studies have shown that the cells migrate in the spinal cord, into the injury site and surrounding cord, providing a "trail" of OEG cells through which axons can grow.

Wise.

[This message was edited by Wise Young on 09-27-03 at 01:32 PM.]

Max · 09-28-2003, 10:19 AM

link

JayHarn3 · 09-28-2003, 02:52 PM

after reading all of this it just makes me wonder if there is any real chance of walking again. everything sounds/looks/seems so complicated that this chair may always be under me...jay

Please get us out of this mess!

Schmeky · 09-28-2003, 03:53 PM

Jay,

I beleive it is possible, but if you follow FDA rules in the US, it is years away. For example:

Phase I Clinical trial takes 6 months to 1 year

Phase II takes 2-4 years or longer, however, this can increase to several years if dosage or the method of delivery has to be changed

Phase III takes 2-4 years and requires duplication

Phase IV is a follow-up for many years to monitor for side effects, etc.

Absolute minimum time: 6-8 years
Typical time: 11-15 years

Therefore, if a SCI therapy begins Phase I in 2007, it would probably be the year 2020 before we could benefit.

09-23-2003, 01:35 AM	#1
dr_bubo Senior Member Join Date: May 2003 Location: Budapest Posts: 377	What happens to the glial scar? Dear Wise, When Lima or Huang is doing their surgery, do they remove or change the glial scar? if yes, what they do, if not, what do you think will happen to it when the OEG cells start to act? Thanks Bubo

09-28-2003, 10:19 AM	#8
Max Senior Member Join Date: Jul 2001 Location: Montreal,Province of Quebec, CANADA Posts: 15,036	ive just posted interesting article about fibroblasts on science news forum link

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09-24-2003, 08:42 AM	#2
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,975	Bubo, if you read the descriptions of the procedures, you will find that neither Dr. Huang nor Dr. Lima removes the "glial scar". None of the animal studies that implanted OEG into the spinal cord did anything about glial scars. I personally am not convinced that glial scars provide a mechanical obstacle to axonal regeneration in the spinal cord. Even if the scars were important, there is nothing much that we can do about it. To my knowledge, there is no treatment that has been successful in preventing glial scars other than cell transplants (including OEG) which have been reported to reduce glial scar formation. Wise.

09-27-2003, 05:19 AM	#4
dr_bubo Senior Member Join Date: May 2003 Location: Budapest Posts: 377	[ if the scars were important, there is nothing much that we can do about it. Wise, Why can't glial scars be removed with laser?[/QUOTE] I heard that there is a chondro..something ABC which removes the scar... was it ever tested on human? if it does, anyone plan to try it before planting OEG and compare the results without this enzyme? Bubo

09-27-2003, 08:30 AM	#5
EAA Senior Member Join Date: Sep 2003 Posts: 238	I understand that Dr. Lima does remove a small amount of glial scar at the two ends of the injury. He does not try to remove all the scar but he does cut in an opening for the new cells.

09-27-2003, 09:05 AM	#6
George78 Senior Member Join Date: Aug 2001 Location: Spain Posts: 245	New hope for the paralysed as scientists re-grow spinal cords (Filed: London Telegraph 13/07/2003) Thirty years of research culminate in a 'Eureka!' moment for a French biologist working to regenerate severed nerve endings, reports Kim Willsher in Paris. French scientists have discovered a way to regenerate damaged spinal cords in a breakthrough that might eventually allow paralysed people to walk again. They have succeeded in regrowing the broken spinal cords of mice after identifying and eliminating two proteins that create scar tissue. This had prevented nerve endings from repairing themselves. When the scientists, from the French National Health and Medical research institute, manipulated the genes of the mice so that they did not produce these proteins, they discovered that the spinal cord regrew within weeks, enabling the animals to run around again. Until now the regeneration of nerve cells - or neurones - in the brain and the spinal column has been considered impossible. Previous attempts to restore locomotion by connecting the two extremities of a severed spine have always failed. The research team is now working on ways of using the discovery to develop a treatment for humans. Prof Alain Privat, 59, who led the team of biologists from the Languedoc University of Science in Montpellier, in the south of France, told The Telegraph yesterday: "It's a very important breakthrough because for the past 100 years researchers working on the regeneration of the central nervous system have been unable to crack this problem. Nobody envisaged being able to repair the system because for a very long time they thought it was something inherent to the fibres themselves that meant they couldn't grow back and restore movement. "Today, after six years of research, we are sure that we can make them work again if we can stop these two proteins from being produced." The team is now working on adapting the process so that it can be applied first to mice and monkeys whose genes have not been modified, before carrying out tests on human patients. The key will be to find ways to inhibit the two proteins that stop the cord from repairing itself. "We've proved that it is possible, but it's going to take at least five years to find out if the technique can be applied to humans. We can produce mutant mice but not mutant people, so we have to find other ways of tackling these proteins," said Prof Privat. "I cannot be 100 per cent sure it will work on humans but I think the chances are very reasonable. It should work but until we do it we won't be sure." The next stage involves developing a "genetic treatment" that could be applied to a damaged spine to halt the scarring process and stimulate the regrowth of the nerves. The researchers are also looking at whether the regeneration of the neurones can be jump-started in older injuries, enabling paralysed people such as Christopher Reeve, the actor, to benefit. Prof Privat believes that the technique could also be used to treat brain injuries and degenerative conditions such as Parkinson's disease. "The neurons in the brain are very similar to those in the spinal cord," he said. The professor, who is the director of the national health and medical research institute at Languedoc University, has worked with a team of three researchers to try to crack the secret of repairing spinal cord neurones. The team identified two key proteins, Vimentine and Glial Fibrillary Acidic Protein (GFAP). These proteins, they discovered, were produced in large quantities after a spinal injury and formed a scar, described as an impenetrable wire fence, around the damaged nerve endings, preventing messages being transmitted to the brain. Under his guidance, his researchers took 100 ordinary laboratory mice and divided them into four groups. The first was left alone as a control set, the second and third were genetically altered to eliminate one of the proteins, and the last group was "double mutants", lacking the genes that produced both proteins. The mice were all tested for their ability to run on a treadmill before their spines were cut. Prof Privat, 59, said: "After two or three weeks there was a small group of animals that was performing better than the others. After four weeks they were moving their back legs and most of their motor function appeared to have been restored. "We discovered that the control group and those whose genes had been only partially manipulated remained permanently paralysed. However, the mice in which both the proteins had been knocked out had recovered the use of their legs. "When we examined these mice we found that there were no scars on the spinal cord fibres, the nervous system circuitry had been reconstructed and that after four weeks there was almost no remnants of paralysis in their hind legs. "Thanks to this genetic modification the scarring that seems to be the cause of the paralysis didn't happen and the nerve fibres were able to grow back. "He recalled the moment he and his team realised that they had achieved the breakthrough. "It took just a few seconds for us to realise that we had finally done it."It was a real 'Eureka!' moment and I jumped into my office where I had a very old bottle of my favourite Scotch, Glenlivet. I said to the others, "This is the time to crack it open'," Prof Privat added. "It is absolutely ground-breaking. I started working on this subject around 30 years ago and I had finally done it." One of the first problems he faces, however, is finding the estimated £3.5 million ( *5 million) needed to continue the research. Until now, the Montpellier team, hit by French government budget cuts, has relied on cash from private associations dedicated to those paralysed by spinal injuries. He said: "We need a relatively small sum of money. We have these encouraging results but barely the means to go on." The results of the team's research will be published by the National Academy of Sciences, based in Washington, this month.

09-27-2003, 10:09 AM	#7
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,975	Max, Let me try to answer the question: Why can't lasers be used to remove the "scar"? 1. There is no "scar" in the traditional sense of the word in most injured spinal cords. Scar usually means a fibrous tissue made by fibroblasts. In most closed spinal cord injuries, where there is no penetrating wound, what one gets is a proliferation of glial cells at the edges of the injury site. While some scientists have called this a "scar". I disagree with them and don't think that they should use the word scar for glial proliferation. When there is a penetrating wound of the spinal, however, fibroblasts do invade into the spinal cord. The central nervous system will wall off what they consider to be "peripheral" tissues. It does so by having glia proliferate at the borders of wounds, where they eventually form the CNS side of the peripheral/central interface. Glial cells proliferate around cells that they consider to be "outside" of the central nervous system, including, for example Schwann cells. On their side (i.e. the peripheral side), fibroblasts and other cells lay down a thin layer of extracellular matrix that is called the basal lamina. Axons like to grow on basal lamina rather than through them. Also, as Jerry Silver has discovered, proliferating glial cells secrete a substance called chondroitin-6-sulfate proteoglycan (CSPG) and CSPG is known to inhibit axonal growth; chondroitinase is an enzyme that breaks down CSPG and is known to encourage regeneration in cut spinal cord injury (which by the way, is a penetrating wound). Please, I am trying my best to explain this situation so that people do not make the simplistic assumption that a "glial scar" prevents regeneration and that all that one has to do is cut out the "scar". 2. Lasers cannot (at least available ones) do not discriminate between different kinds of cells. CO2 lasers (the most common surgical variety) act by heating up water inside cells and killing them. If you have ever used a laser, you will understand that they are not particularly good as a surgical tool. They kill a lot of cells all around (bystander injury) them due to the heat and they also do not penetrate very deeply. 3. Part of the function of the OEG cells is to provide a permissive environment for axonal growth through the injury site and surrounding spinal cord. The neurosurgeon who is working with Dr. Lima is not "removing" scar when he does a midline myelotomy (cutting along the midline of the spinal cord to minimize cutting across axons). They are just making an opening in the spinal cord so that they can place the nasal mucosa. Dr. Huang avoids touching the injury site altogether. He is injecting the OEG cells into the cord and animal studies have shown that the cells migrate in the spinal cord, into the injury site and surrounding cord, providing a "trail" of OEG cells through which axons can grow. Wise. [This message was edited by Wise Young on 09-27-03 at 01:32 PM.]

09-28-2003, 02:52 PM	#9
JayHarn3 Senior Member Join Date: Aug 2001 Location: Montoursville, PA, USA Posts: 146	after reading all of this it just makes me wonder if there is any real chance of walking again. everything sounds/looks/seems so complicated that this chair may always be under me...jay Please get us out of this mess!

09-28-2003, 03:53 PM	#10
Schmeky Senior Member Join Date: Sep 2002 Location: West Monroe, LA, USA Posts: 3,398	Jay, I beleive it is possible, but if you follow FDA rules in the US, it is years away. For example: Phase I Clinical trial takes 6 months to 1 year Phase II takes 2-4 years or longer, however, this can increase to several years if dosage or the method of delivery has to be changed Phase III takes 2-4 years and requires duplication Phase IV is a follow-up for many years to monitor for side effects, etc. Absolute minimum time: 6-8 years Typical time: 11-15 years Therefore, if a SCI therapy begins Phase I in 2007, it would probably be the year 2020 before we could benefit.