Sox11 promotes endogenous neurogenesis and locomotor recovery in mice spinal cord injury

https://doi.org/10.1016/j.bbrc.2014.02.103Get rights and content

Highlights

  • The expression of Sox11 is increased in the injured spinal cord after SCI.

  • Sox11 expression is located in NSCs and newly-generated neurons after SCI.

  • Over-expression of Sox11 promoted neuronal regeneration after SCI.

  • Over-expression of Sox11 increased expression of BDNF after SCI.

  • Sox11 over-expression promoted locomotor recovery after SCI.

Abstract

We introduced a lentiviral vector containing the Sox11 gene into injured spinal cords of mice to evaluate the therapeutic potential of Sox11 in spinal cord injury. Sox11 markedly improved locomotor recovery after spinal cord injury and this recovery was accompanied by an up-regulation of Nestin/Doublecortin expression in the injured spinal cord. Sox11 was mainly located in endogenous neural stem cells lining the central canal and in newly-generated neurons in the spinal cord. In addition, Sox 11 significantly induced expressions of BDNF in the spinal cords of LV-Sox11-treated mice. We concluded that Sox11 induced activation of endogenous neural stem cells into neuronal determination and migration within the injured spinal cord. The resultant increase of BDNF at the injured site might form a distinct neurogenic niche which induces a final neuronal differentiation of these neural stem cells. Enhancing Sox11 expression to induce neurogenic differentiation of endogenous neural stem cells after injury may be a promising strategy in restorative therapy after SCI in mammals.

Introduction

In mammals, the central nervous system (CNS) is sensitive to mechanical injuries that cause permanent functional deficits. Mechanical forces imparted to the spinal cord can produce an immediate disruption of the tissue, with direct axonal and neuronal injury leading to neuronal death. Neuronal death may occur until hours or days after spinal cord injury (SCI) as a result of ensuing secondary pathological processes. Although a number of strategies have been applied to protect injured spinal cords from secondary pathological processes and promote neuronal survival and synaptic plasticity, no fully restorative therapies currently exist for mammalian SCI [1], [2]. Over the past few decades, the discovery of endogenous multipotent stem cell populations in specialized niches of the adult CNS has fueled interest in regenerative therapies based on the recruitment of endogenous stem or progenitor cells [3], [4]. Investigations with neural stem cells (NSCs) have revealed that endogenous adult spinal cord NSCs can facilitate functional recovery but normally fail to do so efficiently. Accordingly, information regarding the modulation of endogenous NSCs to promote functional recovery would greatly enhance the potential for optimizing regenerative neurogenesis in mammals.

The Sox family of transcription factors is well-established regulators of cell fate decisions and are expressed in a tissue-specific manner during development [5], [6]. In specific, Sox11 is mainly involved in neural development and organogenesis during fetal life and functions in neural progenitor cells that have already been committed to neuronal differentiation during neural development [7], [8]. With development, Sox11 expression decreases and is absent from most normal adult tissues [9]. However, it has been reported that Sox11 expression continues in neurogenic areas of the adult brain [10]. While the exact role of Sox 11 in the adult is not known, there are data demonstrating that Sox11 is up-regulated after neural injury/disease and plays an important role in regeneration [11]. Recently, it has been shown that human glioma-initiating cells lose Sox11 expression and over-expression of Sox11 suppresses tumourigenicity by inducing neuronal differentiation [12]. Based on these findings, we hypothesized that Sox11 might have a modulating role upon endogenous NSCs during regeneration after SCI of mice.

The gene transfer for therapeutic purposes offers a valuable approach for the treatment of SCI. Recombinant lentiviral vectors have proved to be superior to other vectors with regard to gene transfer as they not only provide long-term expression of the therapeutic gene, but also serve as an efficient transducer of non-dividing cells such as neurons [13]. Therefore, in the present study, we introduced a lentiviral vector containing the Sox11 gene into injured spinal cords of mice to evaluate their therapeutic potential for the treatment of SCI.

Section snippets

Animals

Thirty-six female Kunming mice, weighing 30 ± 5 g, were obtained from the Laboratory Animal Center of Shandong University. Mice were bred and housed under standard laboratory conditions at 23 °C with an alternating 12 h light and dark cycle and free access to a commercial diet. All animal experiments were approved by the Shandong University Animal Care Committee.

Lentiviral vectors (LV) vector production

A CD511B (System Biosciences, San Francisco, USA) lentivirus vector expressing enhanced green fluorescent protein (GFP) was constructed to

The expression of Sox11 is increased in the injured spinal cord

We established mouse spinal cord hemisection model. Check whether the right hemicord was thoroughly transected under the stereo microscope (Fig. 1A). We used thirty-six mice with successful hemi-section for subsequent experiments. Expression of Sox11 in the injured spinal cord was assessed using immunohistochemical staining at 3 week after spinal cord hemisection. Sox11 expression was more robust on the injured versus contralateral side and diminished as a function of distance from the site of

Discussion

In the present study, we reported that the expression of Sox11 was increased after SCI and mainly located in ependymal cells lining the central canal and in newly-generated neurons in the spinal cord. There exists evidence from several sources indicating that the ependymal zone of the central canal may serve as a stem cell niche [18]. It had been reported that Sox11 expression is strictly confined to Doublecortin-expressing neuronally committed precursors/immature neurons in the adult brain and

Acknowledgments

This work is supported by the National Natural Science Foundation of China (Grant Nos. 81100919, 81071057, 81100849); the Scientific Research Foundation for Returned Scholars, Ministry of Education of China (21300005451001); Shangdong Province Young and Middle-Aged Scientists Research Awards Fund (BS2010YY041); Shandong postdoctoral fund (201203050).

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