What OEG cells can and cannot do

Wise Young · 08-05-2004, 09:01 AM

I am getting a lot of questions via email from anxious family members who have a loved one with amyotrophic lateral sclerosis, cerebral palsy, and other neurodegenerative conditions, asking whether olfactory ensheathing glial transplants would be beneficial.

Here is a web site created by Ron Doucette the original discover of OEG cells http://duke.usask.ca/~rondouc/ and I have posted A summary of the different kinds of cell-based being tried now in people with spinal cord injury around the world which includes a glossary of some of the terms. Let me try to summarize my answers.

First, olfactory ensheathing glia are not stem cells. I put this in bold type because people don't seem to read it no matter how many times I repeat it. Stem cells produce many different kinds of cells. Olfactory ensheathing glia produce only olfactory ensheathing glia. They do not produce neurons. They do not produce astrocytes. They do not produce oligodendroglia. In short, they are not stem cells.

Second, olfactory ensheathing cells (OEC) and olfactory ensheathing glial cells (OEG) are the just different names for the same cells. I prefer the latter because it is more descriptive and distinguishes these cells from other potentially ensheathing cells that may be present in the nasal mucosa. But, other scientists use OEC. That is their preference.

Third, OEG cells are made by stem cells that are present in the nasal mucosa. They migrate in the olfactory nerve to the olfactory bulb where they take up residence. OEG cells can be isolated from the nasal mucosa or the olfactory bulb. The olfactory bulbs are situated in the base of the brain and is hard to get to. If both olfactory bulbs or nerves are damaged, one loses one's sense of smell. Several groups have claimed that they can grow olfactory ensheathing glia from the nasal mucosa, including Ron McKay-Sims in Brisbane. Carlos Lima in Portugal is transplanting pieces of nasal mucosa which contains many cell types and I don't think that he knows what cell type survives the transplantation. Until such evidence is available, to call these transplants stem cells or olfactory ensheahting glia is not justified. There has not yet been any systematic study of the difference between OEG cells isolated from the nasal mucosa or olfactory bulb.

Fourth, OEG cells cannot replace lost neurons in the brain or spinal cord. Therefore, whatever effect OEG cells may have on neurodegenerative diseases is very unlikely to be due to neuronal replacement. Because both nasal mucosa and olfactory bulbs have stem cells, however, it is possible that some stem cells may be present. In many experiments now, we have never seen a neurons resulting from olfactory ensheathing glial transplants using our cell isolation and preparation method. Since Dr. Huang uses a similar method as us, I doubt that he is transplanting stem cells.

Fifth, OEG cells, however, should migrate in the spinal cord after transplantation and facilitate regeneration. Young OEG cells from fetuses and neonatal animals are known to proliferate both in culture and after transplantation. Therefore, it should be possible to inject a relatively small number of cells into the spinal cord and expect the cells to make more cells and to migrate in the spinal cord. This is why Dr. Huang injects the cells into the cord surrounding the injury site rather than to the injury site itself. There is no need to cut open the spinal cord or to make multiple injections over short distances.

Sixth, OEG cells myelinate axons. We recently showed this in rats. The process takes several weeks in a rat. The OEG cells will myelinate axons in conjunction with endogenous myelinating cells. For example, we found that many axons in spinal cords where one myelin segment is contributed by OEG and adjacent segments are contributed by oligodendroglia.

Seventh, OEG cells secrete and express a number of factors that may promote axonal migration. For example, OEG cells express the cellular adhesion molecules L1 and laminin. Both of these molecules are attractive to axons and should stimulate their growth. A number of laboratories have reported the OEG cells secrete neurotrophins such as glial-derived neurotrophic factor (GDNF) and brain-derived neurotrophif factor (BDNF). Both of these factors may contribute to axonal growth and neuronal survival.

Eighth, while OEG cells migrate, they migrate at best a mm or two a day. Therefore, one should not expect OEG cells to go from the brain into the spinal cord within days or even weeks. Transplantation of OEG cells into the brain, for example, should affect the brain. It is unlikely to affect the brainstem or the spinal cord in a day or two after transplantation. So, the reported early recovery of function in patients with amyotrophic lateral sclerosis within a few days cannot be due to migration of OEG. It is possible that growth factors are transported by cerebrospinal fluid flow from the brain down the spinal cord. Regeneration of axons likewise is slow. Axons probably cannot grow faster than the rate of hair growth, no more than 1-2 mm per day. Therefore, the rapid recovery of function that has been observed in spinal cord injury is very unlikely to be due to axonal regeneration. We have hypothesized that OEG cells may be stimulating existing axons to sprout (i.e. send out short distance processes) and connect to additional neurons. This may be an explanation for some of the rapid improvement in sensory function but this needs to be demonstrated in animal studies.

Ninth, OEG cells are recognized by the central nervous system (CNS) as being part of the central nervous system. The CNS, however, recognizes Schwann cells as foreign cells and astrocytes in the central nervous will wall off these cells and prevent their migration in the tissue.

Tenth, OEG cells transplanted from one individual to another (heterografts) are very likely to be immunologically rejected. The immune system recognizes foreign cells through surface proteins called HLA antigens. The brain and spinal cord is believed to be "immune-privileged" because the blood-brain-barrier (BBB) prevents entry of antibodies and inflammatory cells. Note that BBB is open during the first few weeks after a spinal cord injury. This may account for some of the rapid loss of OEG cells that are transplanted to the spinal cord shortly after injury. Also, while the BBB does reduce antibodies and lymphocyte passage, it does not completely eliminate their entry. In animal studies, OEG heterografts are usually immunologically rejected by 3-4 weeks. We know this because the cells are gone by four weeks after transplantation but giving the animals immunosuppresants (cyclosporin or FK501) will prevent this rejection and allow long-term survival of the cells. It is unclear how long fetal OEG heterografts survive when transplanted into human spinal cord. Some people have speculated that fetal OEG cells would not be rejected so fast because immature cells do not express HLA antigens. Therefore, I have speculated that fetal OEG heterografts may survive several months after transplantation into chronically injured spinal cords.

Eleventh, OEG autografts (i.e. cells that are transplanted from one part to another part of the same individual) should not be rejected immunologically. One would expect autografts to survive longer. Please note that longer survival of OEG may not necessarily be needed to stimulate regeneration.

Twelfth, young (fetal or neonatal) OEG cells are more likely to divide and proliferate faster than adult OEG cells. Adult OEG cells, isolated from either the nasal mucosa or olfactory bulb, do not grow or divide as fast or as long in culture or after transplantation compared to fetal or neonatal OEG cells. We know that both fetal and neonatall OEG can proliferate for months in culture.

In summary, OEG cells are not stem cells. OEG and OEC refers to the same cells. Produced by stem cells in the nasal mucosa, OEG cells migrate in the olfactory nerve and take up residence in the olfactory bulb. While OEG can be isolated from the olfactory bulb and nasal mucosa, the differences between peripheral or central OEG are not well-understood. Whether isolated from nasal mucosa or olfactory bulb, however, OEG cells do not produce neurons in culture or when transplanted into the spinal cord. Therefore, they cannot replace lost neurons in the brain or spinal cord. However, OEG cells have been shown in animals to regenerate and remyelinated axons. OEG are similar to Schwann cells, the cells that myelinate peripheral nerves in that they express similar markers such as L1 and laminin, but the central nervous system recognizes transplanted OEG cells as part of central nervous system, unlike Schwann cells. OEG heterografts are likely to be immune-rejected but this may take time to determine. Young fetal or neonatal OEG heterograpfts may not be as immunogenic as adult and may survive longer. Finally, young and fetal OEG cells are likely to proliferate more and more rapidly than adult OEG cells from the nasal mucosa.

Wise.

Belle · 08-06-2004, 08:45 AM

Thanks Wise, great summary! It answers the questions I had about OEG cells that sent me looking at web sites the other day...

*************
AB wife of T8 complete para

Leo · 08-06-2004, 10:22 AM

Thanks Wise, I just copied it for my doctors and others.

"All you have to decide is what to do with the time that is given you."
Gandolf the Gray

NoDecafPlz · 08-06-2004, 11:06 AM

LOL WISE!

BREATHE!

REPEAT!

Actually this was extremely
helpful. So if I am understanding
One combo might be both stem cells
AND OEG IF implants can happen at the same
time.

Anyway, THANKS WISE!
Joe

Wise Young · 08-06-2004, 02:43 PM

Leo, I would be very interested to hear what other scientists or doctors say. These are my opinions about these cells. Some may disagree. Wise.

Christopher Paddon · 08-07-2004, 12:00 AM

Great summary Wise

Are you able also to summarise what you think are the factors which limit the effectiveness of OEG transplants? Or, are scientists simply not sure yet?

What I'm meaning is that for a mid thoracic injury for example (so as to ignore any neuronal replacement problem for now) what is the best that an OEG graft will offer without being combined with any other therapy (except excercise), and why?

Thanks

Chris

antiquity · 08-07-2004, 02:45 AM

Quote:

...what is the best that an OEG graft will offer without being combined with any other therapy...

OEG transplants via Dr. Huang's present technique has led to the return of 2-4 sensory dermatomes and 1-2 levels of motor recovery in some of his patients.

rdf · 08-07-2004, 04:27 PM

Quote:

Leo, I would be very interested to hear what other scientists or doctors say. These are my opinions about these cells. Some may disagree. Wise

Hi Wise. I'm surprised at the quote above. You say these are your opinions, but haven't your detailed explanation of OEG's been proven factual? How could scientists disagree on what you've posted? Isn't there hard evidence to support your post?

-peace

Wise Young · 08-10-2004, 07:14 AM

rdf, scientists are people. Their interpretation of data may be different from mine. They also may not have access to the same information that I do. For example, here are some potential areas of disagreement:

1. olfactory ensheathing glial cells stimulate regeneration. There are some scientists who don't believe the results of Almudena Ramon-Cueto, Geoffrey Raisman, Manual Nieto-Sampedro, Giles Plant, and others.

2. olfactory ensheathing glial cells myelinate axons. There is in fact a controversy over this issue that our laboratory is in the thick of.

3. Olfactory ensheathing glial cells are rejected from the spinal cord. There are some scientists who think that the cells are not rejected. In our own experiments, we have found them to be rejected every time. This, however, is not the opinion of Ramon-Cueto and others who have not used immunosuppression and claim that the cells remain.

4. Human fetal olfactory bulb contain olfactory ensheathing glia. There are some scientists who believe that cells cultivated from human fetal olfactory bulb are not olfactory ensheathing glia but are neural stem cells.

I think that my statements are based on the best evidence available but there are scientists who disagree with me.

Wise.

rdf · 08-10-2004, 12:35 PM

Thanks Wise. I guess it was naive of me to think scientists would be any different than other people when it came to opinions.

I guess what I wanted to know, does the overwhelming majority of reputable scientists believe as do you?

If not, then there are more obstacles before us than I had thought.

Do you think that the conference in SD Ca. might be a vehicle to enlighten those scientists who disagree with you?

I wish there could be a consensus on OEGs among sci scientists/researchers, as they seem to be one of our best hopes.

If scientists can't agree if the OEGs stimulate regeneration and myelinate axons, assuming they've been given the same data that you have, I am less optimistic than before.

-peace

08-05-2004, 09:01 AM	#1
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,108	What OEG cells can and cannot do I am getting a lot of questions via email from anxious family members who have a loved one with amyotrophic lateral sclerosis, cerebral palsy, and other neurodegenerative conditions, asking whether olfactory ensheathing glial transplants would be beneficial. Here is a web site created by Ron Doucette the original discover of OEG cells http://duke.usask.ca/~rondouc/ and I have posted A summary of the different kinds of cell-based being tried now in people with spinal cord injury around the world which includes a glossary of some of the terms. Let me try to summarize my answers. First, olfactory ensheathing glia are not stem cells. I put this in bold type because people don't seem to read it no matter how many times I repeat it. Stem cells produce many different kinds of cells. Olfactory ensheathing glia produce only olfactory ensheathing glia. They do not produce neurons. They do not produce astrocytes. They do not produce oligodendroglia. In short, they are not stem cells. Second, olfactory ensheathing cells (OEC) and olfactory ensheathing glial cells (OEG) are the just different names for the same cells. I prefer the latter because it is more descriptive and distinguishes these cells from other potentially ensheathing cells that may be present in the nasal mucosa. But, other scientists use OEC. That is their preference. Third, OEG cells are made by stem cells that are present in the nasal mucosa. They migrate in the olfactory nerve to the olfactory bulb where they take up residence. OEG cells can be isolated from the nasal mucosa or the olfactory bulb. The olfactory bulbs are situated in the base of the brain and is hard to get to. If both olfactory bulbs or nerves are damaged, one loses one's sense of smell. Several groups have claimed that they can grow olfactory ensheathing glia from the nasal mucosa, including Ron McKay-Sims in Brisbane. Carlos Lima in Portugal is transplanting pieces of nasal mucosa which contains many cell types and I don't think that he knows what cell type survives the transplantation. Until such evidence is available, to call these transplants stem cells or olfactory ensheahting glia is not justified. There has not yet been any systematic study of the difference between OEG cells isolated from the nasal mucosa or olfactory bulb. Fourth, OEG cells cannot replace lost neurons in the brain or spinal cord. Therefore, whatever effect OEG cells may have on neurodegenerative diseases is very unlikely to be due to neuronal replacement. Because both nasal mucosa and olfactory bulbs have stem cells, however, it is possible that some stem cells may be present. In many experiments now, we have never seen a neurons resulting from olfactory ensheathing glial transplants using our cell isolation and preparation method. Since Dr. Huang uses a similar method as us, I doubt that he is transplanting stem cells. Fifth, OEG cells, however, should migrate in the spinal cord after transplantation and facilitate regeneration. Young OEG cells from fetuses and neonatal animals are known to proliferate both in culture and after transplantation. Therefore, it should be possible to inject a relatively small number of cells into the spinal cord and expect the cells to make more cells and to migrate in the spinal cord. This is why Dr. Huang injects the cells into the cord surrounding the injury site rather than to the injury site itself. There is no need to cut open the spinal cord or to make multiple injections over short distances. Sixth, OEG cells myelinate axons. We recently showed this in rats. The process takes several weeks in a rat. The OEG cells will myelinate axons in conjunction with endogenous myelinating cells. For example, we found that many axons in spinal cords where one myelin segment is contributed by OEG and adjacent segments are contributed by oligodendroglia. Seventh, OEG cells secrete and express a number of factors that may promote axonal migration. For example, OEG cells express the cellular adhesion molecules L1 and laminin. Both of these molecules are attractive to axons and should stimulate their growth. A number of laboratories have reported the OEG cells secrete neurotrophins such as glial-derived neurotrophic factor (GDNF) and brain-derived neurotrophif factor (BDNF). Both of these factors may contribute to axonal growth and neuronal survival. Eighth, while OEG cells migrate, they migrate at best a mm or two a day. Therefore, one should not expect OEG cells to go from the brain into the spinal cord within days or even weeks. Transplantation of OEG cells into the brain, for example, should affect the brain. It is unlikely to affect the brainstem or the spinal cord in a day or two after transplantation. So, the reported early recovery of function in patients with amyotrophic lateral sclerosis within a few days cannot be due to migration of OEG. It is possible that growth factors are transported by cerebrospinal fluid flow from the brain down the spinal cord. Regeneration of axons likewise is slow. Axons probably cannot grow faster than the rate of hair growth, no more than 1-2 mm per day. Therefore, the rapid recovery of function that has been observed in spinal cord injury is very unlikely to be due to axonal regeneration. We have hypothesized that OEG cells may be stimulating existing axons to sprout (i.e. send out short distance processes) and connect to additional neurons. This may be an explanation for some of the rapid improvement in sensory function but this needs to be demonstrated in animal studies. Ninth, OEG cells are recognized by the central nervous system (CNS) as being part of the central nervous system. The CNS, however, recognizes Schwann cells as foreign cells and astrocytes in the central nervous will wall off these cells and prevent their migration in the tissue. Tenth, OEG cells transplanted from one individual to another (heterografts) are very likely to be immunologically rejected. The immune system recognizes foreign cells through surface proteins called HLA antigens. The brain and spinal cord is believed to be "immune-privileged" because the blood-brain-barrier (BBB) prevents entry of antibodies and inflammatory cells. Note that BBB is open during the first few weeks after a spinal cord injury. This may account for some of the rapid loss of OEG cells that are transplanted to the spinal cord shortly after injury. Also, while the BBB does reduce antibodies and lymphocyte passage, it does not completely eliminate their entry. In animal studies, OEG heterografts are usually immunologically rejected by 3-4 weeks. We know this because the cells are gone by four weeks after transplantation but giving the animals immunosuppresants (cyclosporin or FK501) will prevent this rejection and allow long-term survival of the cells. It is unclear how long fetal OEG heterografts survive when transplanted into human spinal cord. Some people have speculated that fetal OEG cells would not be rejected so fast because immature cells do not express HLA antigens. Therefore, I have speculated that fetal OEG heterografts may survive several months after transplantation into chronically injured spinal cords. Eleventh, OEG autografts (i.e. cells that are transplanted from one part to another part of the same individual) should not be rejected immunologically. One would expect autografts to survive longer. Please note that longer survival of OEG may not necessarily be needed to stimulate regeneration. Twelfth, young (fetal or neonatal) OEG cells are more likely to divide and proliferate faster than adult OEG cells. Adult OEG cells, isolated from either the nasal mucosa or olfactory bulb, do not grow or divide as fast or as long in culture or after transplantation compared to fetal or neonatal OEG cells. We know that both fetal and neonatall OEG can proliferate for months in culture. In summary, OEG cells are not stem cells. OEG and OEC refers to the same cells. Produced by stem cells in the nasal mucosa, OEG cells migrate in the olfactory nerve and take up residence in the olfactory bulb. While OEG can be isolated from the olfactory bulb and nasal mucosa, the differences between peripheral or central OEG are not well-understood. Whether isolated from nasal mucosa or olfactory bulb, however, OEG cells do not produce neurons in culture or when transplanted into the spinal cord. Therefore, they cannot replace lost neurons in the brain or spinal cord. However, OEG cells have been shown in animals to regenerate and remyelinated axons. OEG are similar to Schwann cells, the cells that myelinate peripheral nerves in that they express similar markers such as L1 and laminin, but the central nervous system recognizes transplanted OEG cells as part of central nervous system, unlike Schwann cells. OEG heterografts are likely to be immune-rejected but this may take time to determine. Young fetal or neonatal OEG heterograpfts may not be as immunogenic as adult and may survive longer. Finally, young and fetal OEG cells are likely to proliferate more and more rapidly than adult OEG cells from the nasal mucosa. Wise.

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08-06-2004, 08:45 AM	#2
Belle Senior Member Join Date: Jun 2004 Location: NW Ohio Posts: 495	Thanks Wise, great summary! It answers the questions I had about OEG cells that sent me looking at web sites the other day... ************* AB wife of T8 complete para

08-06-2004, 10:22 AM	#3
Leo Senior Member Join Date: Jul 2001 Location: Yankton, South Dakota Posts: 3,876	Thanks Wise, I just copied it for my doctors and others. "All you have to decide is what to do with the time that is given you." Gandolf the Gray

08-06-2004, 11:06 AM	#4
NoDecafPlz Senior Member Join Date: Oct 2003 Posts: 9,490	LOL WISE! BREATHE! REPEAT! Actually this was extremely helpful. So if I am understanding One combo might be both stem cells AND OEG IF implants can happen at the same time. Anyway, THANKS WISE! Joe

08-06-2004, 02:43 PM	#5
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,108	Leo, I would be very interested to hear what other scientists or doctors say. These are my opinions about these cells. Some may disagree. Wise.

08-07-2004, 12:00 AM	#6
Christopher Paddon Senior Member Join Date: Oct 2001 Location: New Zealand Posts: 3,109	Great summary Wise Are you able also to summarise what you think are the factors which limit the effectiveness of OEG transplants? Or, are scientists simply not sure yet? What I'm meaning is that for a mid thoracic injury for example (so as to ignore any neuronal replacement problem for now) what is the best that an OEG graft will offer without being combined with any other therapy (except excercise), and why? Thanks Chris

08-10-2004, 07:14 AM	#9
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,108	rdf, scientists are people. Their interpretation of data may be different from mine. They also may not have access to the same information that I do. For example, here are some potential areas of disagreement: 1. olfactory ensheathing glial cells stimulate regeneration. There are some scientists who don't believe the results of Almudena Ramon-Cueto, Geoffrey Raisman, Manual Nieto-Sampedro, Giles Plant, and others. 2. olfactory ensheathing glial cells myelinate axons. There is in fact a controversy over this issue that our laboratory is in the thick of. 3. Olfactory ensheathing glial cells are rejected from the spinal cord. There are some scientists who think that the cells are not rejected. In our own experiments, we have found them to be rejected every time. This, however, is not the opinion of Ramon-Cueto and others who have not used immunosuppression and claim that the cells remain. 4. Human fetal olfactory bulb contain olfactory ensheathing glia. There are some scientists who believe that cells cultivated from human fetal olfactory bulb are not olfactory ensheathing glia but are neural stem cells. I think that my statements are based on the best evidence available but there are scientists who disagree with me. Wise.

08-10-2004, 12:35 PM	#10
rdf Senior Member Join Date: Jul 2001 Location: Someplace between Nowhere and Goodbye Posts: 12,359	Thanks Wise. I guess it was naive of me to think scientists would be any different than other people when it came to opinions. I guess what I wanted to know, does the overwhelming majority of reputable scientists believe as do you? If not, then there are more obstacles before us than I had thought. Do you think that the conference in SD Ca. might be a vehicle to enlighten those scientists who disagree with you? I wish there could be a consensus on OEGs among sci scientists/researchers, as they seem to be one of our best hopes. If scientists can't agree if the OEGs stimulate regeneration and myelinate axons, assuming they've been given the same data that you have, I am less optimistic than before. -peace