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Rapid induction of genes associated with tissue protection and neural development in contused adult spinal cord after radial glial cell transplantation.

ABSTRACT: Cell-based therapy has been widely evaluated in spinal cord injury (SCI) animal models and shown to improve functional recovery. However, host response to cell transplants at gene expression level is rarely discussed. We reported previously that acute transplantation of radial glial cells RG3.6 following SCI promoted early locomotion improvement within 1 week post-injury. To identify rapid molecular changes induced by RG3.6 transplantation in the host tissue, distal spinal cord segments were subjected to microarray analysis. Although RG3.6 transplantation, reduced activity of macrophages as early as 1-2 weeks post-injury, the expression levels of inflammatory genes (e.g., IL-6, MIP-2, MCP-1) were not decreased by RG3.6 treatment as compared to medium or other cell controls at 6-12 h post-injury. However, genes associated with tissue protection (Hsp70 and Hsp32) and neural cell development (Foxg1, Top2a, Sox11, Nkx2.2, Vimentin) were found to be significantly up-regulated by RG3.6 transplants. Foxg1 was the most highly induced gene in the RG3.6-treated spinal cords, and its expression by immunocytochemistry was confirmed in the host tissue. Moreover, RG3.6 treatment boosted the number of Nkx2.2 cells in the spinal cord, and these cells frequently co-expressed NG2, which marks progenitor cells. Taken together, these results demonstrate that radial glial transplants induced rapid and specific gene expression in the injured host tissue, and suggest that these early responses are associated with mechanisms of tissue protection and activation of endogenous neural progenitor cells.

SUBMITTER: Chang YW

PROVIDER: S-EPMC2848950 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Rapid induction of genes associated with tissue protection and neural development in contused adult spinal cord after radial glial cell transplantation.

Chang Yu-Wen YW Goff Loyal A LA Li Hedong H Kane-Goldsmith Noriko N Tzatzalos Evangeline E Hart Ronald P RP Young Wise W Grumet Martin M

Journal of neurotrauma 20090701 7

Cell-based therapy has been widely evaluated in spinal cord injury (SCI) animal models and shown to improve functional recovery. However, host response to cell transplants at gene expression level is rarely discussed. We reported previously that acute transplantation of radial glial cells RG3.6 following SCI promoted early locomotion improvement within 1 week post-injury. To identify rapid molecular changes induced by RG3.6 transplantation in the host tissue, distal spinal cord segments were sub ...[more]

PMID: 19257808

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Project description:Weight-bearing stepping, without supraspinal re-connectivity, can be attained by treadmill training in an animal whose spinal cord has been completely transected at the lower thoracic level. Repair of damaged tissue and of supraspinal connectivity/circuitry following spinal cord injury in rat can be achieved by specific cell elimination with radiation therapy of the lesion site delivered within a critical time window, 2-3 weeks postinjury. Here we examined the effects of training in the repaired spinal cord following clinical radiation therapy. Studies were performed in a severe rat spinal cord contusion injury model, one similar to fracture/crush injuries in humans; the injury was at the lower thoracic level and the training was a combined hindlimb standing and stepping protocol. Radiotherapy, in a similar manner to that reported previously, resulted in a significant level of tissue repair/preservation at the lesion site. Training in the irradiated group, as determined by limb kinematics tests, resulted in functional improvements that were significant for standing and stepping capacity, and yielded a significant direct correlation between standing and stepping performance. In contrast, the training in the unirradiated group resulted in no apparent beneficial effects, and yielded an inverse correlation between standing and stepping performance, e.g., subject with good standing showed poor stepping capacity. Further, without any training, a differential functional change was observed in the irradiated group; standing capacity was significantly inhibited while stepping showed a slight trend of improvement compared with the unirradiated group. These data suggest that following repair by radiation therapy the spinal circuitries which control posture and locomotor were modified, and that the beneficial functional modulation of these circuitries is use dependent. Further, for restoring beneficial motor function following radiotherapy, training seems to be crucial.

Project description:BackgroundSpinal cord injury (SCI) can cause paralysis and serious chronic morbidity, and there is no effective treatment. Based on our previous experimental results of spinal cord fusion (SCF) in mice, rats, beagles, and monkeys, we developed a surgical protocol of SCF for paraplegic human patients. We designed a novel surgical procedure of SCF, called sural nerve transplantation (SNT), for human patients with lower thoracic SCI and distal cord dysfunction.MethodsWe conducted a clinical trial (ChiCTR2000030788) and performed SNT in 12 fully paraplegic patients due to SCI between T1 and T12. We assessed pre- and postoperative central nerve pain, motor function, sensory function, and autonomic nerve function. Conduction of action potentials across the sural nerve transplant was evaluated. Neural continuity was also examined by diffusion tensor imaging (DTI).ResultsAmong the 12 paraplegic patients enrolled in this clinical trial, seven patients demonstrated improved autonomic nerve functions. Seven patients had clinically significant relief of their symptoms of cord central pain. One patient, however, developed postoperative cord central pain (VAS: 4). Five patients had varying degrees of recovered sensory and/or motor functions below the single neurologic level 1 month after surgery. One patient showed recovery of electrophysiologic, motor-evoked potentials 6 months after the operation. At 6 months after surgery, DTI indicated fusion and nerve connections of white cord and sural nerves in seven patients.ConclusionSNT was able to fuse the axonal stumps of white cord and sural nerve and at least partially improve the cord central pain in most patients. Although SNT did not restore the spinal cord continuity in white matter in some patients, SNT could restore spinal cord continuity in the cortico-trunco-reticulo-propriospinal pathway, thereby restoring in part some motor and sensory functions. SNT may therefore be a safe, feasible, and effective method to treat paraplegic patients with SCI. Future clinical trials should be performed to optimize the type/technique of nerve transplantation, reduce surgical damage, and minimize postoperative scar formation and adhesion, to avoid postoperative cord central pain.Clinical trial registration[http://www.chictr.org.cn/showproj.aspx?proj=50526], identifier [ChiCTR2000030788].

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Rapid induction of genes associated with tissue protection and neural development in contused adult spinal cord after radial glial cell transplantation.

Publications

Rapid induction of genes associated with tissue protection and neural development in contused adult spinal cord after radial glial cell transplantation.

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