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  • Author or Editor: Nicholas C. Bambakidis x
  • By Author: Miller, Robert H. x
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Nicholas C. Bambakidis, Rui-Zhen Wang, Linda Franic and Robert H. Miller

Object

The glycoprotein molecule sonic hedgehog (Shh) has been shown to play a critical role in neuraxial development. To assess its role in the repair of demyelination following spinal cord injury (SCI), escalating doses of Shh were injected into demyelinated lesions in adult rat spinal cords.

Methods

Twenty-seven adult rats underwent thoracic laminectomy and chemical demyelination of the spinal cord dorsal columns without neurological deficit. A subset of 20 rats was treated after 3 days by direct injection of Shh at two different doses. Rats were killed at 7 or 21 days after SCI, and tissue samples underwent immediate fixation or were placed into cell culture. Diffuse cellular proliferative responses throughout the gray and white matter were observed in up to 70% of Shh-treated rats. Proliferation around the central canal, believed to be derived from the ventricular ependyma consistent with neuronal stem cell induction, was demonstrated in up to 60% of the treated rats. No significant proliferation in these areas was detected in control rats. Dorsal areas of nestin-positive cells were also observed in 70% of rats treated with high doses of Shh, and these observations were reproduced in cell culture as well as in cultures of dorsal spinal cord explants. Cell counts revealed significant increases in the percentage of oligodendrocyte precursors and neurons in treated compared with control rats.

Conclusions

Exogenous Shh administration promotes nestin-positive cell proliferation after SCI in adult rodents. These cells are believed to be derived from neural precursor cells. The populations of oligodendrocyte precursors and neurons were likewise increased in Shh-treated rats, suggesting that these cells may be derived from neural stem cells.

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Nicholas C. Bambakidis, Nicholas Theodore, Peter Nakaji, Adrian Harvey, Volker K. H. Sonntag, Mark C. Preul and Robert H. Miller

The continuous regeneration of glial cells arising from endogenous stem cell populations in the central nervous system (CNS) occurs throughout life in mammals. In the ongoing research to apply stem cell therapy to neurological diseases, the capacity to harness the multipotential ability of endogenous stem cell populations has become apparent. Such cell populations proliferate in response to a variety of injury states in the CNS, but in the absence of a supportive microenvironment they contribute little to any significant behavioral recovery. In the authors' laboratory and elsewhere, recent research on the regenerative potential of these stem cells in disease states such as spinal cord injury has demonstrated that the cells' proliferative potential may be greatly upregulated in response to appropriate growth signals and exogenously applied trophic factors. Further understanding of the potential of such multipotent cells and the mechanisms responsible for creating a favorable microenvironment for them may lead to additional therapeutic alternatives in the setting of neurological diseases. These therapies would require no exogenous stem cell sources and thus would avoid the ethical and moral considerations regarding their use. In this review the authors provide a brief overview of the enhancement of endogenous stem cell proliferation following neurological insult.

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Nicholas C. Bambakidis, Mary Petrullis, Kui Xu, Brian Rothstein, Ioannis Karampelas, Youzhi Kuang, Warren R. Selman, Joseph C. LaManna and Robert H. Miller

Object

Sonic hedgehog (Shh) is a glycoprotein molecule that has been shown to be associated with the proliferative capacity of endogenous neural precursor cells during embryonic development. It has also been shown to regulate the proliferative capacity of neural stem cells in the adult subventricular zone (SVZ), which are also upregulated in animal models of ischemic stroke. In the present study, the effects of exogenous administration of intrathecal Shh protein were examined in the setting of a rodent model of ischemic stroke, with particular attention given to endogenous neural stem cell proliferation and migration as well as inducible differences in behavioral recovery.

Methods

A rodent model of ischemic stroke was created using the intraluminal suture method of reversible middle cerebral artery occlusion. Animals were treated with intrathecal administration of Shh protein at 24 hours after the onset of the stroke. Behavioral testing was performed, and the animals were killed for measurements of infarct volume 7 days after stroke. Immunohistochemical staining was performed and measurements of cellular proliferation were obtained, with a focus on the proportion and distribution of neural progenitor cells in the SVZ. These values were compared across experimental groups.

Results

Treatment with intrathecal Shh protein resulted in significant improvement in behavioral function compared with the control group, with a significant reduction of ischemic tissue in the cerebral hemisphere. An increase of nestin immunoreactive cells was observed along the SVZ.

Conclusions

Intrathecal Shh agonist at doses that upregulate spinal cord GLI1 transcription increases the population of neural precursor cells after spinal cord injury in adult rats. Intrathecal administration of Shh protein appears to have a neuroprotective effect in animal models of ischemic stroke and is associated with improved behavioral recovery, which may be related to its effects on neurogenesis in the SVZ and could be associated with improved functional recovery.