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Cellular and molecular strategies to overcome macrophage-mediated axonal dieback after spinal cord injury

Busch, Sarah Ann
http://rave.ohiolink.edu/etdc/view?acc_num=case1252273911

Abstract Details

2009, Doctor of Philosophy, Case Western Reserve University, Neurosciences.
Spinal cord injury initiates the processes of inflammation and glial scar formation that ultimately lead to regeneration failure. Interestingly, injured axons not only fail to regenerate, they retract back from the original site of axotomy over time. This phenomenon, also known as axonal dieback, coincides with the infiltration of activated macrophages into the lesion center. Our laboratory has previously shown that activated macrophages directly induce retraction of dystrophic axons in an in vitro model of the glial scar. Here we utilized this model to investigate the basic biology underlying this phenomenon and discovered that several treatments which have been primarily thought to increase neuronal regeneration actually derive a portion of their positive effects from prevention of macrophage-mediated axonal retraction. Treatment with an inhibitor of matrix metalloproteinase-9 ameliorated retraction and identified a critical protease involved in macrophage-mediated axonal dieback in vitro. Digestion of the inhibitory proteoglycan substrate with chondroitinase ABC also prevented macrophages from inducing axonal retraction. Augmentation of the intrinsic growth potential of the neurons with a conditioning lesion prevented macrophage-mediated axonal dieback both in vitro and in vivo. The regenerating front of axons is typically found in areas containing large numbers of activated macrophages, despite the fact that these cells directly induce axonal retraction. In order to investigate this paradox, we analyzed the cellular components of the glial scar and found that in these areas devoid of reactive astrocytes, there is an association of injured axons with a population of cells expressing the precursor markers nestin, vimentin, and NG2 proteoglycan. The influence of NG2+ cells on regeneration is highly controversial, but our in vivo analysis suggests that these cells are permissive to injured axons. We observed the interactions between dystrophic adult sensory neurons and primary NG2+ cells derived from the adult mouse spinal cord and found that NG2+ cells expressed high levels of growth-promoting molecules and were able to stabilize axons undergoing macrophage-mediated axonal dieback. Overall, we have identified several cellular and molecular components of the glial scar that may be critical targets for preventing the phenomenon of macrophage-mediated axonal dieback in the injured CNS.
Jerry Silver, PhD (Advisor)
Gary Landreth, PhD (Committee Chair)
Susann Brady-Kalnay, PhD (Committee Member)
Lynn Landmesser, PhD (Committee Member)
172 p.
Biology; Neurology
spinal cord injury; axonal injury; macrophage; growth cone; dystrophy; conditioning lesion; axonal dieback; NG2; proteoglycan

Recommended Citations

Citations

  • Busch, S. A. (2009). Cellular and molecular strategies to overcome macrophage-mediated axonal dieback after spinal cord injury [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1252273911

    APA Style (7th edition)

  • Busch, Sarah. Cellular and molecular strategies to overcome macrophage-mediated axonal dieback after spinal cord injury. 2009. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1252273911.

    MLA Style (8th edition)

  • Busch, Sarah. "Cellular and molecular strategies to overcome macrophage-mediated axonal dieback after spinal cord injury." Doctoral dissertation, Case Western Reserve University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1252273911

    Chicago Manual of Style (17th edition)

case1252273911
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© 2009, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.