Congress of Neurological Surgery Poster 2005
Sunday, 28 February 2010 21:01
| Title: | A Novel Pathogenic Mechanism in Syringomyelia: Disruption of a Gliogenic Stem/Progenitor Cell Niche |
| Authors: | Milan Radojicic, MD; Gabriel I. Nistor, MD; Hans S. Keirstead, PhD |
| Abstract: | Chronic spinal cord injury (SCI) can lead to an insidious decline in motor and sensory function in individuals even years after the initial injury and is accompanied by a slow and progressive cytoarchitectural destruction. Oftentimes, a cystic cavitation of the central spinal cord, known as syringomyelia, develops and is thought to be initiated by altered CSF hydrodynamics near the site of injury. At present, no pathological mechanisms satisfactorily explain the ongoing degeneration. Here, we undertook a contusion model of rat chronic spinal cord injury in hopes of elucidating some novel features of the disease. In order to model chronic SCI, moderate spinal contusion injuries were induced in ten adult Sprague-Dawley rats weighing 200-250g at T9 using an Infinite Horizon contusion device. All surgical interventions and pre- and post-operative care were conducted in accordance with institutional guidelines. Animals were housed for 18 months then sacrificed for histological analysis. In five animals, BrdU, a marker for the S phase of cell cycle, was administered over a two week period (100mg/kg i.p daily) prior to sacrifice. All animals received a lethal overdose of anesthetic and then were perfused intracardially with 4% glutaraldehyde for resin processing and histological analysis or 4% paraformaldehyde for light microscopy and immunohistochemistry. In this contusion model of rat chronic spinal cord injury, we documented progressive enlargement of the central canal lumen rostral to the epicenter of injury that was accompanied by proliferation of the surrounding ependymal region cells up to a critical diameter, but the central canal lumen nevertheless remained patent. Expansion of the central canal beyond this critical diameter resulted in ependymal cell ciliary loss and a general thinning of the ependymal region, reminiscent of the ependymal cell changes seen in chronic hydrocephalus. Moreover, expansion of the central canal beyond this critical diameter also resulted in a decrease of ependymal region cell proliferation, as judged by BrdU immunolabeling, as well as frequent disruptions of the ependymal region cell layer and adjacent gray matter that were accompanied by macrophage infiltration and extensive gliosis. Ependymal cells have long been known to play an important role in regulating fluid and electrolyte shifts between the CSF and neuropil and have been noted to proliferate after spinal cord injury. Recently, the ependymal region of the spinal cord has also been shown to contain stem/progenitor cells capable of gliogenesis, homologous to the neurogenic subventricular zone of the brain and in keeping with the notion of the central canal as a rudimentary "fifth" ventricle. Indeed, reports of new ependymal cells, astrocytes, microglia and oligodendrocyte precursors arising from the ependymal region have appeared in the literature. Glia are supportive cells of the nervous system that are necessary for maintaining the structural and functional integrity of the spinal cord in the face of injury. Therefore, we present the progressive disruption of the ependymal region, through distensile and cytotoxic means, as a heretofore unrecognized pathogenic mechanism in spinal cord injury that results in impaired gliogenesis, which may ultimately upset the balance between injury and repair in the spinal cord and lead to a vicious cycle of cavitary expansion. As a corollary, we suggest investigations of this basic disease mechanism -- the mechanical and cytotoxic disruption of a stem cell niche -- as a basis for understanding degenerative phenomena in other tissues, ranging from impaired neurogenesis in the brain to the formation of aneurysms in blood vessels. In conclusion, these studies document progressive ependymal region destruction as a critical trigger point in the pathogenesis of chronic spinal cord injury and identify the ependymal region as a novel therapeutic target, through cellular rescue or replacement. Moreover, restoration of favorable CSF hydrodynamics in spinal cord injury, through the inhibition of dural fibrosis, duraplasty and/or CSF shunting techniques, may be necessary to prevent the formation of intraspinal cysts, as would the elimination of a driving force sufficient to propagate the cysts, such as the transient hypertensive episodes of autonomic dysreflexia. This, we believe, would provide an environment more hospitable for repair. |
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| Format: | Digital Poster |