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Thread: The good news: Olfactory ensheathing glial cells from the nose regenerate the spinal cord

  1. #71
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    DA and Jeff,

    The following citations make for interesting background study on olfactory mucosa for regenerative applications. The last two or three might be relevant to your discussion. In addition to OEGs, olfactory mucosa is reported to contain a stem cell type and two neural progenitors. To be honest, I don't think anyone has ever tried to isolate, culture, and therapeutically test each of the olfactory mucosa's cell types for SCI applications. However, since nature saw fit to place the cells in close proximity in their natural setting perhaps they exert an as-of-yet incompletely understood combined synergistic effect? Nevertheless, the following papers include some interesting points:

    1. That OEGs derived from mucosa sources appeared to have equal regenerative effects as those harvested from the olfactory bulb.

    2. That olfactory neurons are noted for their "rapid regeneration" throughout adulthood.

    3. That olfactory neurons emit a feedback signal that limits stem cell or progenitor neural development according to local demands. Since olfactory neurons are not found in the spinal cord, possibly the absense of these limiting signals could partially explain reports of functional gains through olfactory mucosa clinical use sooner than we've been led to expect (based on regeneration initiated by other means).

    4. Mackay from Australia takes pains to point out that OEGs "promote" axonal growth. Since axonal growth is not regeneration, but rather it's the growth of already existing axons, and since stem cells, some precursors, and OEGs often secrete growth factors, and since the hallmark of olfactory regeneration is its "rapid" neuronal replacement, is it not possible the poorly understood coctail of cells in the olfactory mucosa may exert unexpected regenerative effects?


    Of course, this is all conjecture. The clinicans in Portugal and Australia are moving into new, uncharted scientific territory. At this point it's too soon to either dismiss unexpected claims, or attribute them to poorly understood factors. Even if rats react a certain way to olfactory mucosa, there's no guarantee that humans will echo their results, which is true of all new methods and treatments, and why we test new methods in clinical trials no matter how certain a new treatment may seem in rats. So for now the best we can probably say is the jury is still out concerning exactly what's causing these trial's results. But at any rate, I'm really glad they're being conducted and have results to report!


    Lu J, Feron F, Mackay-Sim A, Waite PM. Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord. Brain. 2002 Jan;125(Pt 1):14-21.

    Perry C, Mackay-Sim A, Feron F, McGrath J. Olfactory neural cells: an untapped diagnostic and therapeutic resource. The 2000 Ogura Lecture. Laryngoscope. 2002 Apr;112(4):603-7.

    Roisen FJ, Klueber KM, Lu CL, Hatcher LM, Dozier A, Shields CB, Maguire S. Adult human olfactory stem cells. Brain Res. 2001 Jan 26;890(1):11-22.

    Sacerdote de Lustig E, Josiowicz AD. [Olfactory mucosa: a continuous source of neurons] Medicina (B Aires). 2001;61(5 Pt 1):621-4. Review. Spanish. PMID: 11721332

    Calof AL, Mumm JS, Rim PC, Shou J. The neuronal stem cell of the olfactory epithelium. J Neurobiol. 1998 Aug;36(2):190-205. Review.

    Huard JM, Youngentob SL, Goldstein BJ, Luskin MB, Schwob JE. Adult olfactory epithelium contains multipotent progenitors that give rise to neurons and non-neural cells. J Comp Neurol. 1998 Nov 2;400(4):469-86.

    Sicard G, Feron F, Andrieu JL, Holley A, Mackay-Sim A. Generation of neurons from a nonneuronal precursor in adult olfactory epithelium in vitro. Ann N Y Acad Sci. 1998 Nov 30;855:223-5.

    Goldstein BJ, Fang H, Youngentob SL, Schwob JE. Transplantation of multipotent progenitors from the adult olfactory epithelium. Neuroreport. 1998 May 11;9(7):1611-7.

    Feron F, Mackay-Sim A, Andrieu JL, Matthaei KI, Holley A, Sicard G. Stress induces neurogenesis in non-neuronal cell cultures of adult olfactory epithelium. Neuroscience. 1999 Jan;88(2):571-83.

    Zehntner SP, Mackay-Sim A, Bushell GR. Differentiation in an olfactory cell line. Analysis via differential display. Ann N Y Acad Sci. 1998 Nov 30;855:235-9.

    Lu J, Ashwell K. Olfactory ensheathing cells: their potential use for repairing the injured spinal cord. Spine. 2002 Apr 15;27(8):887-92. Review.

    Calof AL, Bonnin A, Crocker C, Kawauchi S, Murray RC, Shou J, Wu HH. Progenitor cells of the olfactory receptor neuron lineage. Microsc Res Tech. 2002 Aug 1;58(3):176-88.

    Bartolomei JC, Greer CA. Olfactory ensheathing cells: bridging the gap in spinal cord injury. Neurosurgery. 2000 Nov;47(5):1057-69. Review.

    James Kelly

    [This message was edited by James Kelly on Oct 10, 2002 at 08:58 PM.]

  2. #72
    Member iyerraj's Avatar
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    Dr. Young,
    If there is loss of sense of smell because of a frontal/temporal cerebral contusion, is this definitely due to damage to the olfactory bulb, or is there a chance that the mucosa will be affected?
    If the OEG trials evolve into a cure it will be heartbreaking if she is told "can't find any OEG cells in you, your mucosa is all gone".

    Raj

  3. #73
    Jim, I agree.

    Raj, The most common cause of any loss of smell after a brain injury is damage to the olfactory nerve where it passes through the cribiform plate. This is a part of the skull with holes in it that allow the olfactory axons to pass through. If the nerve is sheared at the level of the plate (which is relatively common), scar formation blocks the openings in the cribiform plate and prevents olfactory axonal regeneration. The mucosa should remain intact but I don't know what happens to the olfacotry ensheathing glial cells when the olfactory nerve has been injured and prevented from regenerating. This would actually be a very interesting research topic for a PhD student.

    Wise.

  4. #74
    Senior Member Jeff's Avatar
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    Jim

    Thanks for the information. Hopefully there are synergistic effects from the different cell types in the mucosa. THat would be another plus in addition to its more easily accessed location.

    I know Dr. Huang will be doing more patients and carefully documenting their progress. He will also be randomizing participants to either of two therapies. One will be the current fetal OEG therapy and I'm not sure if he's decided on the other. I think we'll be getting great information as he continues his work. Not about the application of nasal mucosa but at least about fetal OEG. Hopefully the continued work in Portugal will be meticulous also and the patients will get better rehab after surgery. Sure would be nice to see consistent return of function.

    ~See you at the SCIWire-used-to-be-paralyzed Reunion ~

  5. #75
    Since axonal growth is not regeneration, but rather it's the growth of already existing axons,
    It has always been my understanding that regeneration was stimulating existing axons into growing. I have always been under the impression that curing would involve three stages:

    1. Regeneration: Getting damaged axons to grow and/or reducing inhibitory hurdles so they would grow.

    2. Remyelinization: Remyelinating the axons that are intact but lack myelin and also remyelinating the new growth of the axons spurred into growing again.

    3. Neuronal replacement: Replacement of actual neurons (gray matter) in the spinal cord that have died.

    Someone correct me if I missed something somewhere. I hesitate to post his because Jim Kelly is always right and will probably call me an ignorant fool if I am wrong about regeneration. But for the sake of clarity, please advise. Thank you.

  6. #76
    Senior Member Jeff's Avatar
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    Ann

    Regrowth of severed axons is what is commonly referred to as "regeneration." It includes regrowing them past the site of injury. It also means having them connect with useful targets on the other side in order for the regeneration to benefit us.

    I'm not exactly sure what distinction Jim was making below but I think you definitely have the right idea in your post.

    ~See you at the SCIWire-used-to-be-paralyzed Reunion ~

  7. #77
    Ann, the word regeneration has been used loosely. In traditional biological terms, regeneration refers to the "regrowth of lost or destroyed parts, or organs." http://www.dictionary.com/search?q=regeneration

    When biologists referred to limb regeneration, they are talking about regenerating the limb which is a multicellular structure and there is both axonal regeneration and cellular replacement going on.

    In the case of spinal cord injury, the word "regeneration" usually refers to axons, regrowing the part that has been damaged. This is cellular or axonal regeneration. Obviously, if the neuron is lost, there is nothing to regenerate from or to... the usual term is neuronal "replacement" rather than neuronal regeneration.

    Wise.

  8. #78
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    Ann and Jeff,

    I apologise if my point about regeneration and regrowth was confusing (and especially if it was incorrect). The point I was trying to make was that olfactory mucosa may offer benefits on multiple fronts, including specialized cell replacement, axon regrowth (from existing neurons), remyelination, and lesion scaffolding. But the distinction between regeneration and regrowth is a minor one. My memory was probably at fault, but I had thought that Dr. Young once corrected me when I used "regeneration" to describe regrowing axons. So in the interest of accuracy I made the distinction. Like I said, apparently I was mistaken.

    Btw, I may have also picked up this misconception from misunderstanding the work of Anton Usala. In explaining his method of inducing embryogenesis in mesenchymal tissues, he had explained regeneration as the reinactment of early developmental processes, especially regarding the replacement of damaged or destroyed cells. He contrasted the re-generation of replacement cells against the growth of existing cells as separate processes. Probably I read more into this explanation that what was intended.

    I apologise, Ann, and thanks for setting me straight!

    James Kelly

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