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Thread: Activity of implanted stem cells or OEG

  1. #11
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    Wise,

    I know that my questions can be difficult sometimes, but I'm also confronted with interrogations concerning the recoveries after the laserponcture sessions, and understanding some phenomena gives me food for thought.

    In the second paragraph of your answer concerning animal studies, you suggest that 3 scenarios are possible if we inject neonatal OEG cells into rat spinal cord:
    a) The inflammatory environment of the injury secretes toxins (?), which kills the neonatal OEG cells shortly, and if they are injected above or below the injured site of the spinal cord, they survive better;
    b) They migrate straight into the injury site and die immediately;
    c) They migrate in the cord but avoid the injury site, which induces that neonatal OEG cells have an intrinsic "immune intelligence" in relation to the surrounding inflammatory environment.

    The first observation is that an early transplant of OEG cells may not be desirable; the injury site should "cool down." It seems that the adult OEG are more resistant and less sensitive to the inflammatory environment.
    The immune rejection is one of the major problems encountered in OEG transplantation, and the association of anti-inflammatory or immunosuppressant may be a solution but what about the toxicity induced for the OEG cells?? or other cells?

    The early effects observed after the implantation remains a mystery so far, secondary decompression has been proposed as a possible explanation.

    The OEG cells action as a growth factor for surviving axons in the injury site is also an interesting field, which may open up unsuspected new horizons in the next months.

    But my curious nature urges this question: are we sure that there will be compatibility between these new restored nerve cells and the original nervous impulse each of us has. The questions I have kept asking myself is: we know that voluntary order is the outcome of two factors: the order (the nervous impulse) and the tissue carrying the information (the spinal cord) which carries the order and spreads it to the targets; so shouldn't there be compatibility between these two actors such as biological compatibility, biochemichal compatibility, biomagnetical compatibility or bioelectrochemical compatibility?

    Every individual's biological composition is unique, which is why immunosuppressant have to be used in the case of implantation, i.e. when we impose the body a foreign body by default and / or obligation.

    But here, we have two different data:
    a) The tissue carrying the information (nervous impulse), which is a solid matter;
    b) The nervous impulse, which is a virtual entity as nobody, to date, has ever managed to put a nervous impulse in a test tube.

    I've always taken into account the issue of compatibility in my works too. I have chosen to study the carried information only (i.e. the order) and not the tissue carrying it, which adapts itself to its new post-injury plasticity. For instance, in case of paraplegia caused by a virus, the spinal cord is intact in the MRIs but there's still no function: it's the diffusion of the nervous impulse which is disturbed.

    It's also a path that will have to be explored one day. Do we need a restored nervous tissue to carry the nervous impulse? Our 20 years of observations have suggested us : "why not?"

    It is a frantic race run by researchers to free the spinal cord individuals from their wheelchair. We may wish to take up Baron Pierre de Courbertin�s words, resuscitator of the modern Olympic Games: "The important is to participate..."

    Albert
    -----------------
    French:

    Wise,

    Je sais que mes questions sont parfois difficiles, mais etant moi-meme confronte a des interrogations concernant les recuperations apres les seances de laserponcture, je cherche des pistes de reflexion et de comprehension de certains phenomenes.

    Dans le 2e paragraphe de votre reponse, vous suggerez que dans les etudes animales, dans le premier cas de figure des OEG neonatales de rat ont ete injectees et il s'est passe 3 scenarii :
    a) Soit l'etat inflammatoire de la blessure secrete des toxines (?), ce qui tue rapidement les OEG neonatales et si elles sont injectees a distance de la lesion, elles survivent mieux.
    b)Soit elles migrent directement vers le site lesionnel et elles meurent tout de suite
    c) Soit elles migrent mais a distance du site lese et evitent le site lesionnel, ce qui induit chez les OEG neonatales une forme intrinseque "d'intelligence immunitaire" par rapport a l'environnement inflammatoire.

    La premiere constatation est qu'une implantation precoce d�OEG n'est peut-etre pas souhaitable, il faut laisser "refroidir" le site lesionnel. Les OEG adultes sont plus resistantes et moins sensibles a l'environnement inflammatoire, semble-t-il.
    Le rejet immunitaire est un des grands problemes que peut rencontrer l'implantation d'OEG, et l'association d'un anti-inflammatoire et d'anti-rejets peut etre evoque comme une piste mais quelle toxicite pour les OEG ?? ou pour d'autres cellules ?

    Les effets precoces observes apres l'implantation reste un mystere pour l'instant, la decompression secondaire a ete evoquee comme possible.

    L'action des OEG comme facteur de croissance des axones survivants dans le site lesionnel est aussi une piste interessante et les mois prochains nous ouvrirons peut-etre des horizons insoupconnes.

    Mais, mon petit cote curieux me pousse a poser une question : sommes-nous sur qu'il y aura compatibilite entre ces nouvelles cellules nerveuses restaurees et l�influx nerveux originel de chacun. La question que je me suis toujours posee est la suivante : la commande volontaire est la rrsultante de deux facteurs : l'ordre (l'influx nerveux) et le tissu porteur (la moelle �pini�re) qui conduit l'ordre et le diffuse a ses cibles. Ne faut-il pas qu'il y ait compatibilite entre ces deux acteurs : compatibilite biologique, biochimique, voire biomagnetique ou bioelectromagnetiques ?

    Chaque individu est unique dans sa composition biologique, c'est ce qui oblige a utiliser des anti-rejets en cas de transplantation, c'est-a-dire imposer au corps un corps etranger par defaut et / ou par obligation.

    Mais ici nous sommes en presence de deux donn�es diff�rentes :
    a) Le tissu porteur (tissu nerveux), matiere solide,
    b) L'influx nerveux, entite virtuelle car personne n'a reussi a ce jour a mettre de l'influx nerveux dans une eprouvette.

    Cette question de la compatibilite a toujours ete presente au cours de mes travaux aussi, j'ai choisi de ne m'interesser qu'a l'information portee (l'ordre) et non pas au tissu porteur qui s'adapte a sa nouvelle plasticite post-lesionnelle. Par exemple, en cas de paraplegie par attaque virale, la moelle �pini�re est intact a l'IRM mais il n'existe aucune commande : c'est la diffusion de l'influx nerveux qui est perturbe.

    C'est aussi une piste qui un jour meritera etre exploree plus avant. Avons-nous besoin d'un tissu nerveux restaure pour conduire l'influx nerveux ? Nos observations, apres 20 ans de recherche nous suggerent "pourquoi pas ?"

    Dans cette course effrenee que les chercheurs se livrent pour delivrer les blesses medullaires de leur fauteuil, il faut faire sienne la parole du Baron Pierre de Coubertin, reanimateur des Jeux Olympiques modernes : "L'important, c'est de participer..."
    Albert

  2. #12
    Albert,

    Most scientists are now of the opinion that the acutely injured spinal cord may not be the best place to transplant cells, including OEG and stem cells for several reasons. First, the inflammatory environment of the injury site and the signals that it is emanating is that of injury. This prompts stem cells to produce astrocytes (gliosis). Second, the inflammatory environment does seem to be damaging to cells that have receptors to pro-inflammatory cytokines such as TNF-alpha. Third, the inflammatory environment attracts many inflammatory and immune cells. Thus, the cells can initiate a systemic immune response to the transplanted cells and lead to earlier immune rejection.

    I don't think that decompression and untethering of the spinal cord explains the early recovery for the following reasons. First, Dr. Huang (at least in the first 200 or so patients) insisted that all of them are decompressed on untethered at least 6 months before he will transplant OEG cells into them. Second, while some of the patients recovered some function after the decompression/untethering procedure, the response to untethering and decompression is not as consistent or as good as he is observing in patients that receive OEGs. Third, in the last six months or so, Dr. Huang has been doing keyhole laminectomies to expose a small part of the spinal cord above and below the injury site, using these openings to inject the cells into the spinal cord without exposing the injury site. Thus, he is not exposing, decompressing, or untethering the spinal cord in these patients. I don't think that his results have changed.

    Your "curious nature" question concerning compatability of the "new restored nerve cells" and the original nervous impulse" puzzles me. Axons carry the signal. The OEG cells themselves are not carrying the signals. In animals, OEG cells are improving the signals by stimulating axonal growth across the site or remyelination of axons that have crossed the site. I am suggesting that it may also be stimulating plasticity in the spinal cord, allowing axons that have survived or grown across to reconnect with neurons.

    Immune response is actually quite complex. How the body's immune system recognize self from foreign invaders depends on many factors. The first is that the immune system must be primed to recognize the foreign cells. Generally, it does so by recognizing tissue compatability antigens that are expressed on the surfaces of cells. If the tissue is matched for such antigens, often the immune response is blunted. If the system is never stimulated to mount an immune response, it may not do so. Of course, in the central nervous system, the immune systems take longer to get out and get back in. Therefore, it may be possible that Dr. Huang's approach, emphasizing atraumatic injection of the cells into the chronically injured spinal cord, reduces the opportunity for immune responses.

    Regarding your example, viral infections may damage the spinal cord in various ways. It may cause demyelination of the axons, direct degeneration of the axons, or degeneration of the motoneurons. Even though the spinal cord may look "intact" on MRI, there may be damage to the axons. Action potentials are conducted by individual axons and do not "diffuse" in the tissue. Conduction may be disturbed by demyelination since myelin is necessary for action potentials to conduct reliably and rapidly in axons.

    Wise.

  3. #13
    I have been thinking about this semi-critically for the past few days [specifically, OEG and early recovery] and believe that what happens after transplantation -- in the abstract, anyway -- is fairly simple. In short, I believe that the early recovery seen from transplantation of OEG cells proves the fact that the CNS does try to regenerate and/or rewire itself after injury and that something is just blocking the regrowth.

    Now how to explain it... :cracks neck:

    Stream of concious, here goes.

    Plasticity [in this instance] is the ability of the nervous system to rewire itself so that some nerves change "jobs." This rewiring likely works through dendrites and axons detaching and forming new connections. Dendrites are able to synthesize proteins. The most likely reason, because of efficiency, is that the proteins they synthesize control their local synapses. Olfactory nerves in the nose should have a pretty high turnover rate. This high turnover rate [loss of neurons, forming new ones] would mean that the "helper" cells would have to be pretty efficient at telling axons and dendrites how to reconnect relatively quickly. Since OEGs are essentially "helper" cells, they should be able to code for the proteins that cause the synaptic plasticity that Dr. Young references below in addition to their ensheathing properties. Once the OEGs are transplanted aboce and below the injury site, they act as amplifiers or repeaters that allow the guidance cues to survive longer/further. Basically, they allow new synapses to form.

    Dr. Young, have you noticed a correlation between the density/number of surviving axons that cross the injury site and the likelihood of regeneration across it?

    -Steven

  4. #14
    Steven,

    Good questions but no good answers. I agree with you that the early recovery after OEG transplants suggests that OEG cells are contributing to the "plasticity" and rewiring of the system so that the recovery can occur.

    Question: Is there a correlation between the density/number of surviving axons and the likelihood of regeneration? The answer is that we still cannot really (or at least not in a way that is convincing to the scientific community) tell the difference between regenerated and surviving axons. So, there is no convincing answer to this question.

    Question: Is there regeneration going on spontaneously in the spinal cord? A positive answer to this question will require a tour de force scientific war. Although many scientists have accepted the fact that the central nervous system is capable of regeneration, acceptance that there is spontaneous regeneration accounting for some of the recovery that occurs in animals and people after spinal cord injury is a much more difficult task. All the Schwab had to do was show that IN-1 allowed some axons to regrow and this was associated with some functional recovery. The demonstration that there is spontaneous recovery requires rigorous identification of regenerated and surviving axons, the demonstration that there is regeneration in the untreated spinal cord, and that this regeneration is associated with recovery.

    I believe that the evidence is in front of our eyes. First, a vast majority (<70%) of people with spinal cord injury recovery at least 1 to 2 segments of motor and sensory function, a process that sometimes takes 6 or more months. Second, people with incomplete spinal cord injuries during the first days after injury often recover very substantially, i.e. average of 79% of what they had lost. Third, there are many axons that with endbulbs bordering the injury site. For a long time, scientists considered these to be axons that are "sterile" and are no longer growing. Jerry Silver and others have been proposing that these are "frustrated growth cones" and represent axons that are constantly trying to grow across the injury site.

    Traditional methods of demonstrating regeneration are not very helpful because they really rely on having complete transection of the spinal cord, so that any fiber that crosses the injury site must have regenerated.

    Wise.

  5. #15
    "Originally posted by Wise Young:

    Question: Is there a correlation between the density/number of surviving axons and the likelihood of regeneration? The answer is that we still cannot really (or at least not in a way that is convincing to the scientific community) tell the difference between regenerated and surviving axons. So, there is no convincing answer to this question."

    Would you be willing to make as educated of a guess as is possible as to whether or not their is a correlation?

    "The demonstration that there is spontaneous recovery requires rigorous identification of regenerated and surviving axons, the demonstration that there is regeneration in the untreated spinal cord, and that this regeneration is associated with recovery."

    Highly doubtful, but is there a way to injure the spinal cord without causing gliosis?

    -Steven

  6. #16
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    Is the spontaneous regeneration indicating that the cells die fast. Maybe, there is a method to constantly feed the cells for a period of time. The new cells would be continually replacing the cells that die unil there is regeneration.

  7. #17
    steven, I am not convinced that gliosis really prevents regeneration per se. The reason that I say is because gliosis is an essential part of spinal cord injury repair. Let me explain further because almost everywhere I turn the term "glial scar" turns out, even amongst people who ought to know better.

    Glia serve an essential purpose of separating central nervous tissues from peripheral tissues. So, for example, glia cover and form the tight junction around blood vessels in the brain and spinal cord. They send processes called "endfeet" that cover every square micron of blood vessel surfaces. The endfeet from different glia join each other in connections called "gap junctions" so that material can transfer from endfeet to end feet. All materials that transfer across an intact blood-brain or blood-cord barrier must go through glial endfeet.

    Glial cells proliferate to surround any cell that they recognize as being "peripheral" in origin. Thus, for example, if Schwann cells are transplanted, glia immediately recognize them as being peripheral and surround them, producing a thin layer of laminin, fibronectin, and chondroitin-6-sulfate proteoglycans (CSPG) that surround them. Likewise, if any fibroblast (skin cells that produce scars) gets into the spinal cord (and they usually do if there is penetrating wound in the spinal cord and the surgeon neglects to repair the dura), astrocytes immediately wall them off. When this happens, it is true that astrocytes forms a glial scar. However, when there is a contusion injury of the spinal cord, such a glial scar seldom forms.

    Most scientists who do spinal cord injury models with penetrating wounds talk about glial scars because that is what they see. However, scientists who study contusion injuries of the spinal cord seldom talk about glial scars because, although there is gliosis around the injury site, a "glial scar" seldom develops.

    Most of the studies that have shown regeneration in the spinal cord have not and do not address the problem of gliosis or glial scar. For example, an axon typically will grow relatively well in an area that is populated by most astrocytes. Kawaguchi, in fact, believes that having glia provide a bridge at the injury site is good and he has been repairing transected and hemisected spinal cords by placing some embryonic astrocytes into the cut. He believes that the presence of such cells during the first few days after a cut is useful... He has a different theory as to why this is the case but I think that this may be because having an abundance of astrocytes in an area prevent invasion of fibroblasts which would form a "glial scar".

    Wise.

  8. #18
    Originally posted by T-Bone:

    Is the spontaneous regeneration indicating that the cells die fast. Maybe, there is a method to constantly feed the cells for a period of time. The new cells would be continually replacing the cells that die unil there is regeneration.
    T-bone, there are many stem cells in the spinal cord. That is one of the reasons why perhaps transplantation of neural stem cells into the spinal cord may not be all that helpful. After spinal cord injury, many of the cells in the spinal cord start to divide. The proliferating cells of course involve progenitor cells (cells that produce specialized cells such as astrocytes and oligodendroglia) but many scientists believe that the proliferating cells include stem cells. Several of the therapies for spinal cord injury are aiming directly at stimulating endogenous stem cells to proliferate (produce more cells). For example, this is apparently what AIT-082 (this went through clinical trial in acute spinal cord injury this past year) and possibly inosine do.

    Interestingly, John Gearhart and others have transplanted fetal stem cells into the spnal cord of mice that have the gene for amyotrophic lateral sclerosis (ALS) a primary motoneuron degeneration disease. He found that the cells invaded into the spinal cord and intercalated themselves into the gray matter of the spinal cord, and may secrete some factors that prevent or slow down degeneration of motorneurons and other neurons. The mice that had the fetal stem cells (derived from germ cells) transplants survived longer with less neurological deficits that those that did not. This is of course in a motoneuronal degenerating disease.

    In spinal cord injury, particularly in the contusion model, many studies have now shown that there may be neuronal and oligodendroglia apoptosis (programmed cell death) in the cord surrounding the injury site. The former occurs during the first several weeks while the latter continues to occur as the spinal tracts that have been cut off their cell bodies undergo degeneration. Many of the acute and subacute spinal cord injury therapies being investigated by scientists now are aiming at preventing this secondary cell death.

    I am sorry that this does not answer your question directly but I was taking the opportunity to expound about cell death. I also sense that you may be mixing up regeneration and cell replacement. The concept of spinal cord regeneration applies mainly to regenerating axons that have been damaged. Replacement of cells is different and will require stem cell therapies. Stem cells can either be implanted or endogenous stem cells can be stimulated to produce more stem cells. Because stem cells migrate in the body, one should think of a pool of itinerant stem cells (sort of like wandering carpenters) going to where there is damage and fixing things up.

    Wise.

  9. #19
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    Wise,
    Thanks for your answer.
    I think that we must give these things time and see what embryonic or adult OEGs can tell us on spinal cord repair.

    jv,
    We'll be very happy to see you again, please let us know which period exactly.
    It will be a test in real conditions with OEG cells (Dr Lima's procedure) and laserponcture. We hope that this double therapy will bring about the progress hoped.

    Albert

  10. #20
    "However, scientists who study contusion injuries of the spinal cord seldom talk about glial scars because, although there is gliosis around the injury site, a "glial scar" seldom develops."

    Thanks for the clarification. What changes do occur in a contusion type injury?

    -Steven

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