Abstract
BackgroundNeural stem cells for the treatment of spinal cord injury (SCI) are of particular interest for future therapeutic use. However, until now, stem cell therapies are often limited due to the inhibitory environment following the injury. Therefore, in this study, we aimed at testing a combinatorial approach with BDNF (brain-derived neurotrophic factor) overexpressing early neural progenitors derived from mouse embryonic stem cells. BDNF is a neurotrophin, which both facilitates neural differentiation of stem cells and favors regeneration of damaged axons.MethodsMouse embryonic stem cells, modified to stably express BDNF-GFP, were differentiated into PSA-NCAM positive progenitors, which were enriched, and SSEA1 depleted by a sequential procedure of magnetic-activated and fluorescence-activated cell sorting. Purified cells were injected into the lesion core seven days after contusion injury of the spinal cord in mice, and the Basso mouse scale (BMS) test to evaluate motor function was performed for 5 weeks after transplantation. To analyze axonal regeneration the anterograde tracer biotinylated dextran amine was injected into the sensorimotor cortex two weeks prior to tissue analysis. Cellular differentiation was analyzed by immunohistochemistry of spinal cord sections.ResultsMotor function was significantly improved in animals obtaining transplanted BDNF-GFP-overexpressing cells as compared to GFP-expressing cells and vehicle controls. Stem cell differentiation in vivo revealed an increase of neuronal and oligodendrocytic lineage differentiation by BDNF as evaluated by immunohistochemistry of the neuronal marker MAP2 (microtubule associated protein 2) and the oligodendrocytic markers ASPA (aspartoacylase) and Olig2 (oligodendrocyte transcription factor 2). Furthermore, axonal tracing showed a significant increase of biotin dextran amine positive corticospinal tract fibers in BDNF-GFP-cell transplanted animals caudally to the lesion site.ConclusionsThe combinatorial therapy approach by transplanting BDNF-overexpressing neural progenitors improved motor function in a mouse contusion model of SCI. Histologically, we observed enhanced neuronal and oligodendrocytic differentiation of progenitors as well as enhanced axonal regeneration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0268-x) contains supplementary material, which is available to authorized users.
Highlights
Neural stem cells for the treatment of spinal cord injury (SCI) are of particular interest for future therapeutic use
The only moderate improved function could possibly be explained by the fact that not enough Embryonic stem cell (ESC) have differentiated into the required specialized cell type or that cell replacement was not sufficient to compensate for the limited regeneration potential of the spinal cord
In vitro differentiation and purification of ESCs Mouse ESCs were differentiated into early neural progenitor cells (NPCs), which express PSA-NCAM as a marker
Summary
Neural stem cells for the treatment of spinal cord injury (SCI) are of particular interest for future therapeutic use. In this study, we aimed at testing a combinatorial approach with BDNF (brain-derived neurotrophic factor) overexpressing early neural progenitors derived from mouse embryonic stem cells. BDNF is a neurotrophin, which both facilitates neural differentiation of stem cells and favors regeneration of damaged axons. Diverse cell types have been tested already in transplantation studies in SCI animals, such as Schwann cells, olfactory ensheathing cells, mesenchymal stem cells, and embryonal stem cells [2]. None of these cell types led to a striking functional motoric improvement. By using BDNF-secreting fibroblasts or by viral delivery, BDNF was shown to have a positive effect on axonal regeneration [14,15,16,17] and to enhance the integration of transplanted embryonal precursor cells [18]
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