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Thread: Regeneration vs Cell Replacement Therapies

  1. #1

    Regeneration vs Cell Replacement Therapies


    It seems to me that there is some confusion concerning spinal cord regeneration and cell replacement. Let me try to comment on these two goals and some therapies relevant to these goals of spinal cord injury research. I have written this fairly rapidly and ask forgiveness for typographical and grammatical errors.


    Regeneration usually refers to regrowth of something that has been partially damaged. For example, when one talks about regenerating part of the body, the body is still assumed to be present. Likewise, when one is regenerating an organ, part of the organ is still present. In general, when scientists talk about neural regeneration, they are talking about regrowing part of a neuron that is still alive. Neurons in the brain and lower spinal cord send axons that respectively descend and ascend in the spinal cord. Injury to the spinal cord damages the axons but usually leaves the neurons of origin intact. However, the part of the axon that has been cut off from the neuronal cell body usually dies. Therefore, the process of regeneration is the regrowth of the axon across the injury site and all the way to the neurons that it originally made contact with.

    Many therapies have been reported to regenerate the spinal cord. One category of therapies include drugs or antibodies that inhibit a family of molecules called Nogo. Nogo is usually expressed in normal myelin (the membrane that surrounds axons and is made by a cell called oligodendroglia). When growing axons encounter Nogo, they stop growing. For many years, Nogo was considered to be the primary obstacle to regeneration in the central nervous system. However, much data now suggest that several other class of molecules may inhibit axonal growth. For example, a family of extracellular proteins called chondroitin-6-sulfate-proteoglycan (CSPG) will inhibit axonal growth and an enzyme called chondroitinase ABC that breaks down CSPG will stimulate regeneration in mammalian spinal cords. Growth factors also contribute to regeneration and these include neurotrophins such as glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), neutrophic factor 3 (NT-3), and nerve growth factor (NGF). Recent studies suggest that the intracellular cAMP governs the response of axons to growth inhibitors. Many other therapies have been reported to stimulate regeneration, including inosine, alternating electrical currents, cell adhesion molecules such as L1.

    Axons don't like to grow across empty spaces. The injury site may be bereft of molecules that support axonal growth. Axons grow on surfaces and they are attracted to cell adhesion molecules for which they have receptors. Growing axons express a cell adhesion molecule called L1 and this molecule has been shown to stimulate regeneration in contused spinal cords. Another approach is to transplant cells that express such cell adhesion molecules. For example, olfactory ensheathing glia (OEG) cells obtained from the nose or the olfactory bulb express a variety of cell adhesion molecules such as laminin and L1. Schwann cells likewise express laminin and L1 and therefore provide attractive substrates for axonal growth across the injury site. Finally, recent studies indicate the increasing cAMP levels in the spinal cord with a phosphodiesterase-4 inhibitor Rolipram and injecting a cAMP analog into the spinal cord will markedly stimulate regeneration in the spinal cord, when combined with Schwann cell or bone marrow stem cell transplants.

    Regenerated axons must not only cross the injury site but they must grow all the way from the injury site to neurons present in the lower spinal cord in the case of motor axons and to neruons in the brainstem or brain in the case of sensory axons. Axons grow very slowly, typically no faster than the rate of hair growth, probably less than a mm per day. Given this slow rate of growth, regeneration of axons may take many months or even years. Note that in the case of cervical spinal cord injuries, the distance of motor axonal growth from the cervical spinal cord to the lower spinal cord may exceed 500 mm while the distance of sensory axonal growth to the brainstem and brain may be 50-100 mm. The expectation is faster recovery of sensory function and slower recovery of motor function for regenerative therapies of cervical spinal cord. However, the reverse is true for injuries to the lower thoracic spinal cord where sensory axons may have to grown 500 mm or longer while motor axons only have to grow 100 mm or less.

    In summary, regeneration of axons is a major objective of spinal cord injury therapies. Many therapies have been shown to regenerate axons. If and when it occurs, regeneration should be relatively slow and may take months to years. Treatments that block growth inhibitors present in the spinal cord, cell transplants that improve the environment of the injury site for axonal growth, and growth factors and other therapies that stimulate axonal regeneration have been shown to improve locomotor recovery in animals. If the neurons that give rise to the axons are damaged or the neurons that the axons connect do are damaged, there may limited numbers of axons or limited targets to which the axons can connect to. In such cases neuronal replacement therapies are required.

    Cell Replacement

    Trauma kills cells in the spinal cord, at the injury site and often above and below the injury site. Until recently, most scientists believed that the central nervous system cannot replace neurons. If true, it means that the neurons we die with are the same cells that we were born with. As we age, the number of neurons should decline. Likewise, if we injure our central nervous system, there may be precipitous losses of neurons in the brain and spinal cord. However, much evidence in the past decade indicate that neurogenesis (the creation of new neurons) occur throughout adult life in parts of the brain. There is still some controversy whether neurogenesis occurs in the cortex and the spinal cord but there is strong evidence that neurogenesis occurs in the hippocampus and olfactory bulb.

    In spinal cord injury, three types of neuronal loss may occur. First, trauma or ischemia kills neurons in the gray matter at the injury site or where the ischemia occurs. This is particularly problematical in the cervical or lumbosacral enlargement where most of the neurons that control the arms and legs respectively are situated. Second, damage to the axons, particularly when the damage is situated close to the neurons, may kill the neurons from which the axons originate. Some neurons in the cortex and the brain and brainstem may die after spinal cord injury. For example, neurons in the red nucleus, the sources of the rubrospinal tract, undergo atrophy and sometimes death after spinal cord injury. Several studies suggest that local administration of neurotrophins can prevent death and reverse atrophy of rubrospinal neurons. Third, the target neurons that the axons connect to may die as a result of loss of denervation. This too has been claimed but evidence that target spinal neurons die is very limited. However, damage to motoneuronal axons in spinal roots or peripheral nerve will lead to atrophy of muscles to which the axons connect.

    Loss of neurons reduces the number of axons that can regenerate and the number of targets to which they will connect. The latter, in particular, is problematical for many people with cervical or lumbosacral spinal cord injuries. Please note that the spinal cord ends at vertebral level L1, even though the spinal roots continue to go down the spinal canal below L1 and exit the appropriate openings of the L1-L5 and S1-S5. The L1 spinal cord is situated about T10, L2-L5 spinal cord at T11-T12 vertebral levels, and the S1-S5 spinal cord is situated at L1 vertebral canal. So, trauma or ischemia to T10-L1 may result in loss of neurons that control the legs. Likewise, trauma or ischemia to the cervical spinal cord will kill neurons that control the arms and hands, as well as phrenic respiratory neurons at C3-4. Because the upper thoracic spinal cord contains relatively little gray matter, damage to neurons is usually minor in such cases and involve only local neurons responsible for chest and abdomenal muscles.

    Trauma or ischemia also damage cells called oligodendroglia. These cells myelinate axons in the brain and spinal cord. Most rapid-conducting axons in the spinal cord are myelinated. Myelin consists of membranes wrapped many times around axons, providing a form of "insulation" that allows myelinated axons to conduct much more rapidly than unmyelinated axons. In the central nervous system, cells called oligodendroglia myelin between 15-20 axons. Trauma to the spinal cord will damage oligodendroglia and the inflammation of the spinal cord can cause oligodendroglial apoptosis, both of which will result in demyelination. Various infectious diseases, autoimmune, and inflammatory diseases may cause demyelination as well. Although the spinal cord contains stem cells that can produce new oligodendroglia, remyelination may be incomplete. Also, regenerated axons need to be myelinated. Thus, myelination is important for functional recovery.

    Many therapies have been shown to remyelinate the spinal cord after injury. One is to transplant oligodendroglial precursors, embryonic or neural stem cells that produce oligodendroglial precursors. A second approach is to provide growth factors that stimulate oligodendroglial precursors to grow and myelinate axons. This includes factors such as neuregulin. A third approach is to transplant peripheral myelinating cells into the central nervous system. For example, both Schwann cells and olfactory ensheathing glia have been reported to myelinate axons in the spinal cord. Both of these cells have been transplanted into the spinal cord of humans. There is very strong incentive for such research because it wold be beneficial not only for people with spinal cord injury but also people with multiple sclerosis and other demyelinating diseases.

    Neuronal replacement is more difficult to do. In the spinal cord, two types of neurons are present: interneurons and lower motoneurons. Interneurons connect to other neurons while motoneurons connect to muscle. Note that there are so-called "upper motoneurons" and these are are situated in the brain and send axons to the spinal cord to connect with either interneurons or motoneurons in the spinal cord. Injury may damage both interneurons and motoneurons in the spinal cord. Many interneurons are inhibitory in function and therefore loss of these neurons may produce increased excitation. Loss of motoneurons results in denervation of muscle. The muscles that the lost motoneurons use to connect to typically will undergo atrophy. Neuronal replacement therapy must not only make new neurons but also get them to connect to the right place.

    Several therapies have may produce new neurons in the spinal cord. The first is fetal neurons. Isolated from fetal brains, fetal neurons or their precursors have been used for some time to treat Parkinson's disease and stroke. A second approach is transplantation of fetal neural stem cells that have the capability of producing a wide range of neural cells including astrocytes, oligodendroglia, and neurons. In the fetus, the stem cell that produces neurons is the radial glial cell. A third approach is transplantation of embryonic stem cells that have been predifferentiated in culture to produce neurons. A recent study from Johns Hopkins showed that such transplants can produce motoneurons that send their axons out of the ventral roots of the spinal cord. A fourth approach is to use adult neural stem cells. Several researchers have shown that adult brain contains neural stem cells that producing neurons. Some scientists have advocated taking adult neural stem cells from one part of the brain and transplant them to another part of the brain or spinal cord but this is rather invasive and begs the question why we do not simply try to stimulate the stem cells to proliferate and migrate to the appropriate sites.

    Post-natal stem cells (e.g. umbilical cord blood and bone marrow mesenchymal stem cells) are pluripotent and can replace neurons and other cells in the spinal cord. Indeed, several researchers have claimed that such cell transplants have beneficial effects on recovery of function, possibly by stimulating remyelination, regeneration, and replacement of neurons. However, although these treatments may be beneficial, evidence that bone marrow or umbilical cord blood cells can produce new and functioning neurons or myelinating cells in the brain and spinal cord is still controversial. One possibility is that these cells are neuroprotective or stimulates endogenous cells in the brain and spinal cord. These issues are likely to be resolved in the near future as many laboratories are now actively investigating these areas.

    In summary, cell replacement therapy is an integral part of the cure for spinal cord injury. Loss of neurons is common after spinal cord injury. Axonal regeneration alone may not be sufficient to restore all function when neurons providing axons and target neurons have been lost or myelin-producing cells are lost. Finally, there may also be a role of stem cells in repairing the spinal cord both in the acute and chronic stages after injury. The exciting possibility is that some cell transplant therapies may be able to stimulate regeneration and replace cells. For example, Schwann cells and olfactory ensheathing glia stimulate regeneration and myelinate spinal axons. Embryonic and fetal stem cells have been shown to produce neurons in the spinal cord. While post-natal stem cells from bone marrow or umbilical cord blood have been shown to be pluripotent, evidence that they produce new neurons in the spinal cord is still limited and controversial. I expect substantial progress in these areas of research in the coming year.

    [This message was edited by Wise Young on 07-27-04 at 11:56 PM.]

  2. #2
    Senior Member MikeC's Avatar
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    Dec 2003
    Tampa, FL
    Dr Young, thanks again for another great summary. Not sure if this is an appropriate question to ask here but how do these therapies differ in chronic vs acute SCI? I'm not even sure what the difference is between chronic and acute but I know in several posts people have mentioned that some therapies will only work in acute or chronic. Thanks again.

    T12 Incomplete - Walking with Walker, Oct 2003

  3. #3
    MikeC, this is really only about chronic. Wise.

  4. #4
    So in other words we are very close.

    And great explanation!

    [This message was edited by QuadPro on 07-27-04 at 08:08 PM.]

  5. #5
    Senior Member DA's Avatar
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    Jul 2001
    beaumont tx usa
    Originally posted by QuadPro:

    So in other words we are very close.
    those words sound familar. i wonder where i hear them before.

  6. #6
    Senior Member
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    Mar 2002

    Excellent description of what is need to restore function after substaining a sci...
    now what?

    Gods speed for a cure~

  7. #7
    Senior Member Jeff's Avatar
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    Jul 2001
    Argao, Cebu, Philippines
    I think an example might be in order. Let's take me. I have a small lesion around C6. Complete regeneration of ascending and descending tracts in the spinal cord might not restore complete function to my triceps and wrists. But I would expect full return of my fingers, trunk, abs, hips, legs, bowel, bladder and sexual function.

    Or, for instance, someone who has a high cervical injury and gets complete regeneration could experience restoration of walking/trunk/abs/b/b/s but not breathing function if there were no undamaged neurons to innervate the phrenic nerves.

    I think thoracic injuries might be less dependent on neuron replacement.

    SCI Research has traditionally focused on neuron protection and regeneration. Within the last few years the concept of neuron replacement has become accepted. We will benefit from both.

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

  8. #8
    Senior Member Rollin Rick's Avatar
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    Nov 2002
    B ville, New York, USA
    Originally posted by DA:

    Originally posted by QuadPro:
    So in other words we are very close.
    those words sound familar. i wonder where i hear them before.
    geez, I heard them words before myself, maybe it was in my dreams?

    What one man can do another can do

  9. #9
    Senior Member
    Join Date
    Mar 2002

    It does sound like you understand how to fix the problem area as of today...

    These things of which you speak about could make it possible for us to attain a cure, right?

    Would you or have you done this yet on any human being or has anyone else? If not this is very sad and i would love to help you help us if you tell me what you need to make this happen.

    My opinion for an effective combination for a cure:

    1) eliminate barries- (scar tissue, NOGO,)

    2) replace lost neurons- (stem cells)

    3) stimultate axonal growth- (GDNF, BDNF, Inosine, NT3, NGF, CNTF,replicons-genetic therapy)

    4) remylination (OEC, Schwan cell or Oligodendrisits)

    5) Snapitic genisis

    6) Intensive PT

    7) these are what i have found to be effective in my personal research within the last year or so, but i am sure there is more that you aware of..??..

    Some of these have been around for decades. We need an effective combonation to restore function and accomplish a cure.

    Gods speed,

    [This message was edited by Superstar on 08-05-04 at 12:57 AM.]

  10. #10
    Wise, thanks a lot for that *great* summary. I understand that we may still have a long way before cells replacement, but, like Susan said, you seem to know perfectly what to do to have major axons sprout and remyelination. Am I wrong?...
    So what are we waiting for?... Money?... Patients?... or a neurosurgeon that understand SCI is a case of emergency and we cannot wait 20 years for phases I, II, III approval?...
    I'm 26 years post, I remember I've been to Washington DC in 1981. There was a neurosurgeon named Carl Kao. He was performing schwann cells graft on humans. 23 years later, you write:
    Schwann cells likewise express laminin and L1 and therefore provide attractive substrates for axonal growth across the injury site.
    ... so what?... Where are we?... I don't know what to say, Wise. This looks like a joke. A joke that lasts 26 years. My life.
    You want another joke?... Do you remember IN-1 and Nogo stuff?... That was *before* 1990. On July 13 2004, 15 years later, Lisa Schnell said:
    Once the anti-Nogo system is shown to be safe in other animal models, the first human patients with spinal cord injuries will be considered for treatment.

    "The first patients we would try this technique on would probably be recently injured young men and women with severe injuries who have no hope of spontaneous recovery," says Schnell.
    Keep smiling, my friends...

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