We performed selective isolation of astrocytes from glial scars at different time points for a gene expression analysis and found that the expression of Sox9 , an important transcriptional factor for glial cell differentiation, was significantly increased in chronic phase astrocytes (CAs) compared to SAs in the sub-acute phase. In addition, we found that Col-I-SAs transplanted into a naïve spinal cord formed glial scar again by maintaining a high expression of genes involved in the integrin-N-cadherin pathway and a low expression of CSPG-related genes.

For their use in trials of spinal-cord injury (SCI) in human beings, specific difficulties that affect the success of clinical trials have to be recognised. First, transection of the spinal cord is commonly applied in animal models, whereas contusion, which generally leads to injury in two to three segments, represents the typical injury mechanism in human beings.

Abstract One of the most obvious deficits following a spinal cord injury is the difficulty in walking, forcing many patients to use wheelchairs for locomotion. Another strategy for improving the walking in spinal cord injured patients is the use of functional electric stimulation of nerves and muscles to assist stepping movements.

Although the cascade of tissue reactions and cell injury develops over a period of days or weeks, the most extensive cell death in SCI occurs within hours of trauma. Based on the NASCIS (National Acute Spinal Cord Injury Study) II and III trials, methylprednisolone (MP) is recommended for the management of SCI.1, 2, 3, 4 These trials showed effectiveness of MP in improving motor scores in patients with SCI compared with placebo.1 However, several lines of evidence have shown that MP therapy within the first 8 hours after SCI failed to result in a statistically significant short-term or long-term improvement in patients’ overall motor or neurologic scores compared with controls who did not receive steroids.5, 6, 7 Moreover, steroid use was significantly associated with an increased risk of hyperglycemia in both randomized controlled trials2 , 8 , 9 and observational studies,10, 11, 12, 13, 14, 15 and pneumonia based on data from observational studies.10, 11, 12, 13, 14, 15, 16 In the light of these observations, the risk/benefit ratio should be carefully considered before initiation of steroid therapy after SCI, and literature advocating routine use of MP after SCI should be strongly reconsidered.

This has resulted in the development of multiple experimental treatment strategies with the collective aim of enhancing and surpassing the limited spontaneous recovery occurring in animal models and ultimately humans suffering from spinal cord or brain injuries. The main challenges in the clinical field of spinal cord repair are associated with the standardization and sensitivity of functional outcome measures, the definition of the inclusion/exclusion criteria for patient recruitment in trials, and the accuracy and reliability of an early diagnosis to predict subsequent neurological outcome.

MD, PhD From the Department of Neurology, Spinal Cord Injury Neuro-Rehabilitation Section, Restorative Treatment and Research Program (D.B., C.L.S., J.W.M.); Center for the Study of Nervous System Injury (D.B., C.L.S., J.W.M.); and Department of Neurological Surgery (J.W.M.), Washington University School of Medicine, St Louis, Missouri Send reprint requests to Dr John W. E-mail: mcdonald@neuro.wustl.edu Buy Abstract BACKGROUND– By affecting young people during the most productive period of their lives, spinal cord injury (SCI) is a devastating problem for modern society.

Summary Spinal cord injury is currently incurable and treatment is limited to minimising secondary complications and maximising residual function by rehabilitation. Improved understanding of the pathophysiology of spinal cord injury and the factors that prevent nerve and tissue repair has fuelled a move towards more ambitious experimental treatments aimed at promoting neuroprotection , axonal regeneration, and neuroplasticity . By necessity, these new options are more invasive.

Studies dealing with the promotion of spinal cord repair and those directed to improve mobility by exploition of neuroplasticity will be summarized. The promises and challenges of translational basic research in rodent SCI models will be presented.

The secondary phase of injury is characterized by ischemia, excitotoxicity, vascular dysfunction, oxidative stress, and inflammation that leads to cell death (Braughler et al., 1985, Rowland et al., 2008, Wagner and Stewart, 1981). The processes in the secondary injury are often harmful to surviving bystander neurons and the injury of these neurons can lead to poor functional recovery (McDonald and Sadowsky, 2002, Vawda and Fehlings, 2013). In addition, it is during the secondary phase that an inhibitory environment is created that impairs endogenous regeneration and remyelination (Dasari et al., 2014). The secondary phase is made up of subphases that are divided temporally into the immediate, acute, subacute, intermediate, and chronic stages of SCI (Fig. 1). The immediate phase lasts for approximately the first 2 h of injury and constitutes the immediate aftermath of the injury (Norenberg et al., 2004). The rapid death of neurons and glia accompanies spinal shock that results in the immediate loss of function at and below level of the injury (Boland et al., 2011, Ditunno et al., 2004). The first sign of the immediate phase is the necrotic cell death of neurons due to ischemia, hemorrhaging, edema, and mechanical disruption of the cell membrane (Kakulas, 2004, Tator et al., 1993). Early in the immediate phase there is upregulation of TNF-α and IL-β (Davalos et al., 2005, David and Kroner, 2011, Donnelly and Popovich, 2008, Pineau and Lacroix, 2007). Another early event that occurs within minutes of SCI is the rise of extracellular glutamate to excitotoxic levels (Park et al., 2004, Wrathall et al., 1996). The immediate phase is not generally considered as a target for treatment as it is too early, clinically speaking, for treatment to be realistically administered. A hallmark of the secondary injury in the acute phase is the vascular disruption and hemorrhage that result in ischemia (Tator and Fehlings, 1991, Tator and Koyanagi, 1997). Although the vascular mechanism that leads to the prolonged ischemia is not fully understood, it is thought that disruption of the microvascular, hypotension, and increased interstitial pressure leads to hypoperfusion of the cord after injury (Kwon et al., 2004, Mautes et al., 2000, Ng et al., 2011, Tator and Fehlings, 1991). The process of hemorrhage and ischemia is closely related to the permeability of the blood–brain-barrier (BBB)/blood-spinal cord barrier (BSCB). SCI results in the permeability of the BBB/BSCB due to the direct mechanical disruption of the vasculature and the effect of inflammatory mediators on endothelial cells (Rowland et al., 2008, Zhang et al., 2012). BSCB permeability in rats reaches its peak 24 h after contusive/clip compression SCI and returns to control levels around 2 weeks after injury (Figley et al., 2014, Noble and Wrathall, 1989). BSCB permeability may be affected by inflammatory cytokines that are commonly upregulated by SCI (Pardridge, 2010, Pineau and Lacroix, 2007, Schnell et al., 1999). Although permeability of the BBB/BSCB after SCI is seen as a deleterious event, the permeability may provide an opportunity to introduce cell treatments and drugs that normally may not be able to cross the BBB/BSCB. The leakiness of the BBB/BSCB permits the infiltration of immune cells, such as T cells, neutrophils, and monocytes, into the CNS.

This has led to great debate in the SCI research community about the Ievei and quality of evidence needed to select truly promising candidate therapies. This article reviews the basis for optimism in the new understanding of the processes of degeneration after SCI and the mechanisms of regeneration.