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Recovery From Spinal Cord Injury Seen In Mice When Scarring Is Minimized

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    Recovery From Spinal Cord Injury Seen In Mice When Scarring Is Minimized

    Recovery From Spinal Cord Injury Seen In Mice When Scarring Is Minimized

    PHILADELPHIA - Severe injury to the spinal cord can lead to devastating loss of function, and subsequent recovery is often minimal. Accordingly, the factors that inhibit recovery have been a major research focus in recent years. Might there be ways to promote regeneration of the cells in the spinal cord or otherwise encourage a restoration of function following injury?
    A new study conducted in mice by researchers at The Wistar Institute suggests that the key to recovery from severe spinal-cord injury may lie in limiting the scarring process that generally follows such an injury, rather than in an enhanced regenerative capacity.

    In mice where the ability of inflammatory cells to reach the injury site was physically limited, the formation of scar tissue at the site was also limited, the scientists found in their experiments. Without the physical barrier of scar tissue to impede their progress, neurons on both sides of the injury site were able to grow and reestablish connections with each other over a period of two to three weeks, leading to substantial recovery of function. A report on the study appears in the February 1 issue of the Journal of Neuroscience Research.

    "The problem in recovery from spinal-cord injury appears to be the scar tissue that forms in response to injury," says Ellen Heber-Katz, Ph.D., a professor at The Wistar Institute and senior author on the study. "The scar eliminates the ability of neurons to regrow their axons across the injury site. It's an absolute physical block. We found, however, that if you prevent the scar tissue from forming, the mice recover from their injuries."

    The findings show that physically preventing scar tissue from forming can open the way for recovery from spinal-cord injury, according the Heber-Katz.

    More clinically relevant, perhaps, is that the research also suggests that drugs able to biochemically block scar-tissue formation immediately following such an injury might have a similarly beneficial effect. Perhaps most tantalizing is the possibility raised by the study that therapies designed to eliminate existing scar tissue at the site of past injuries might also be helpful.

    "In combination with efforts to address the issue of tissue loss that often accompanies injuries to the human spinal cord, this approach might enable us to design an elegant therapy that permits the cord to heal itself," says Alexander Seitz, M.D., a postdoctoral fellow in the Heber-Katz laboratory and lead author on the study.

    To prevent the formation of scar tissue at the site of injury to the spinal cord, the researchers were careful in their experiments to maintain the integrity of the dura, the outer layer of protective membranes that encloses the spinal cord. Doing this left both ends of the damaged cord in close proximity to each other and limited their displacement. It also had the effect of blocking inflammatory cells, particularly the fibroblasts that would normally migrate to the injury site, from being able to reach the site and subsequently proliferate in the gap between the cord ends, leading to scar formation. Scar tissue, a long-lasting protein matrix, is important in the body's response to injury, but it represents an absolute barrier for the axonal growth cones of neurons that might otherwise bridge the injury site.

    In addition to senior author Heber-Katz and lead author Seitz, the remaining author on the Journal of Neuroscience Research study is Elsa Aglow, also at The Wistar Institute.

    The research has been generously funded from its inception by the G. Harold and Leila Y. Mathers Charitable Foundation, a private foundation based in Mount Kisco, NY. Recently, the work has also received substantial funding from the F.M. Kirby Foundation in Morristown, NJ, and the National Institutes of Health.

    The Wistar Institute is an independent nonprofit research institution dedicated to discovering the causes and cures for major diseases, including cancer, AIDS, autoimmune disorders, and other illnesses. The Institute is a National Cancer Institute-designated Cancer Center - one of the nation's first, funded continuously since 1972, and one of only eight focused on basic research. Founded in 1892, Wistar was the first independent institution devoted to medical research and training in the nation. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies, and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.


    Note: This story has been adapted from a news release issued by Wistar Institute for journalists and other members of the public. If you wish to quote from any part of this story, please credit Wistar Institute as the original source. You may also wish to include the following link in any citation:


    Before everybody gets too excited about this, I want to emphasize:

    1. This is a strain of mice with a yet-to-be identified combination of genes that allows it to heal rapidly with minimal scarring.

    2. The pictures and data that I saw was not very impressive and I did not think that it allowed significant walking recovery in the mice.

    3. They had transected that spinal cord and this does lead to collagen and fibroblast scarring in the spinal cord. However, for the vast majority of people with spinal cord injury, such scars do not develop. People and animals with contused spinal cords, the most common kind of spinal cord, develop astrocytosis or gliosis which is not the same kind of scar and really does not stop axonal growth in the same way as collagen-fibroblast based scars.

    There is no treatment here... only a straing of mouse that seems to be able to heal better than other mice. It would be interesting to find out which genes are responsible. It would also be nice to find out why the genes improve recovery.



      Two Questions

      Dr. Young,

      According to the neurosurgeon that did both of my spinal cord surgeries, my cord was only slightly compressed. He said also that the dura was not broken and he decompressed the cord during the first surgery. Does this mean that my cord did not develop a glia scar?

      Also, just out of curiosity given I am an incomplete, if someone is considered a complete but has pain radiating below the injury site isn't that traveling up the cord to the brain thus going through the actual break?


      "Save the last dance for me!"


        Debbie, good questions... Let me answer them briefly and then expand on them as necessary from questions that people ask.

        • Gliosis (I don't like to use the word scar to describe the proliferation of glial cells at the injury site because scar implies fibrosis and the presence of collagenous and fibrotic scars that develop in skin) occurs with all sorts of spinal cord injury, with or without compression. Gliosis occurs with any injury of the brain or the spinal cord. It is part of the repair mechanism of the spinal cord, particularly if the blood brain barrier breaks down. Glia normally line the blood vessels and they are responsible for separating the central nervous system from the rest of the body. If there is damage to the spinal cord, breakdown of the blood brain barrier almost always occurs at the injury site. Glial and other cells proliferate (multiply and produce more glial cells) at the injury site in response to the injury. Many studies have shown that axons do not stop at areas of gliosis because they produce a mechanical barrier to axonal growth. Rather, glial cells secrete a chemical called chondroitin-6-sulfate proteoglycans (CSPG) which tends to inhibit axonal growth. There are several therapies that are aimed at this inhibitory effect of CSPG. One is to use a bacterial enzyme called chondroitinase ABC (CABC) which breaks down CSPG. CABC has been shown to facilitate regeneration of axons when applied to the brain and spinal cord. The other approach is to block an intracellular messenger called rho which stops axonal growth. Lisa McKerracher has reported that a bacterial toxin called C3 will block rho in axons and promote their growth through all sorts of inhibitors. She has formed a company called Bioaxone to develop C3 and variants of the molecules for regnerating the spinal cord.

        • Neuropathic pain. The current theory is that neuropathic pain does not come from pain messages that pass through the injury site. Rather, spinal neurons above the injury site are hyperexcitable and they send messages to the brain. The brain interprets the messages as being from below the injury site. Neuropathic pain occurs with deafferentation (removal of sensory inputs). The neurons that have lost their sensory inputs then sends pain information up to the brain and the brain interpret that information as coming from below the injury site. Altering the excitability of these deafferented neurons is one of the approaches of drug therapies of neuropathic pain. That is why anti-depressive drugs and anti-epileptic drugs help reduce the pain, to some extent. Normally, opioid drugs also modulate the excitability of pain neurons in the brain and spinal cord. However, in spinal cord injury, it appears that the neurons have lost their sensitivity to opioids. Recent research have suggested that this can be changed with some drugs. Likewise, there is much work going on to see if certain specific gene responses of sensory neurons mediate the excitability change of sensory neurons and several laboratories have reported several genes that appear to be necessary for neuropathic pain to develop in animals. I believe that next generation of therapies for neuropathic pain will be involved in suppressing these genes.




          One interesting addition to Dr. Young's list of possible ways of addressing the regeneration-suppressing effect of gliosis...

          According to three published papers by Maureen Condic of the University of Utah (see the NINDS's website, where her work is featured), if an embryonic axon-outgrowth process is properly initiated, the glial scar (with its CSPGs) may not be inhibitory at all! The key to this process is upregulating Integrin expression on neuronal membranes. Remarkably, this process does not involve the use of embryonic or fetal tissue.

          Dr. Condic was recently named a McNight Investigator, which means that her projects have a reliable source of funding. She believes that because of this, her work may move faster than previously expected.
          James Kelly


            Neuropathic Pain

            Dr. Young

            I am inclined to believe that neuropathic pain or CP is not just one type of pain. At least in some individuals, e.g. there is CP above the injury which tends to be a hyper or sharp type of pain and then some individuals have burning pain below the injury.
            Some individuals undoubtedly have a mix of pain types. This makes it very difficult for a researcher to say what is going on. Like with cancer where they made progress by trying to cure each cancer separately, I believe it will be necessary to focus on only one type of pain at a time.

            You talked previously that current theory on CP is leaning to the neurons above the injury sending signals that are interpreted as pain. This does not seem to provide a good explanation of why pain in many individuals is evoked by stimulation below the injury level. Or why, for example, placing a piece of cloth on a thigh or abdomen slowly causes an increase in pain. If you are saying that, in incomplete SCI, the signals reaching the neurons above the injury are interpreted as pain then what you said may be right.

            If it is neurons above the injury sending pain signals then typical painkillers like opioids should work as well as usual. For most CP they dont.

            I have read that sensory neurons are often near the skin surface and that their axons extend up the spinal cord. Also, most injuries, even those categorized as incomplete, have some neurons and axons survive but typically they are injured or diminished in some way, usually demyelinated. This would affect the strength of the signal but also its character. If 100 neurons tell the the brain "A piece of paper is laying on the lap." the brain registers paper. If only 10 neurons send the message over a commensurate area and the signal is somewhat scrambled, the conservative thing for the brain to do is to decide that it is pain. (I subscribe to flight or fight theory of evolution).

            My main points are that:

            CP is more than one type of pain

            It may originate both above or below the injury

            It may be related to the quality of the signal transmitted or the number of signals vice normal

            And, from my earlier post to you, animals are not a good research subject for human CP, they may not perceive it as we do and certainly may not react the way we do.

            What a challenge you researchers face here. I hope I get this next line right.

            "Ad aspera ad astra."

            Joe B
            Joe B


              Thank you

              As always thank you Dr. Young for you explanations. It is certainly wonderful to have a learned person to go to to get answers.

              "Save the last dance for me!"


                Joe B, I cannot agree with you more and greatly appreciate your posting. The issue of whether the pain is instigated by sensory input is important. I find it hard to believe that neurons in the the spinal cord will send messages to the brain without some noxious input from the sensory input from the sensory input to the system. Neurons are like people. Their behavior is influenced by their inputs. Of course, I believe in the individuality of people but I don't think that they will send messages to the brain without some instigating stimuli. I have been puzzled by this probem for years.

                We have all known people who issue complaints without cause. For the record, let me say that does not refer to my wife and colleagues, that every complaint is well justfied and completely justified.

                In my opinion, this is what neuropathic pain is all about. How is it that we have all these cells that are sending pain message to the brain without cause? While we may think of these cells as rogue cells engaging in abnormal behavior, the high incidence of neuropathic pain in spinal cord injury suggest that this is not only false but really something that we must not ignore.

                Neuropathic pain must be mistake of evolution. I have a difficult time imagining any evolutionary advantage to neuropathic pain. Such pain incapacitates people, adding to the disability that they have from paralysis and sensory loss and reduces their survival. Why in the world would did the nervous system evolve the neuropathic pain and then retained it so that it afflicts a majority of people who have had deafferenitation injury?

                Please forgive the speculation that follows because I am trying to express my thoughts on this issue without the traditional inhibitions that restrict scientists from expressing thier musings. However, if I were to respect my training that evolutionary theory, I must analyze the potential beneficial effects of neuropathic pain. One the most superficial level, one can perhaps say that people who complain the most will get the most attention. Perhaps people who complain most vociferousely about their pian are the ones who get the most most attention, the best care, and therefore are most likely to survive would survive to bear the most offsprings.

                On a deeper level, neuropathic pain provides insights into the organization of the pain system. It suggests that the pain is the trashcan of sensations, that pain is what happens when our nervous system cannot decide what the sensory inputs mean. Our nervous system cannot anticipate everything that may be inputted. There may be a tremendous advantage to our central nerosus system to attributing sensations that is not proprioceptive, i.e. thermal or or noxious, to the category of pain.

                It makes sense that the brain interpret all untagged input as pain. After all, anything that the brain cannot recognize must be potentially dangerous to survival. It forces all organisms to establish clear criteria to distinguish between what they recognize and what they don't recognize. The latter is perhaps safest when relegated to pian which drives behavior.