PSA-NCAM positive neural progenitors stably expressing BDNF promote functional recovery in a mouse model of spinal cord injury

Stem Cell Research & Therapy

Julia Leschik³  Beat Lutz³  Jan Baumgart¹  Konstantin Radyushkin²  Kevin Friedemann²  Barbara Fackelmeier³  Robert Nitsch⁴  Nikolai Schmarowski⁴  Tina Zimmermann³  Jennifer Butenschön³ 

[1] Translational Animal Research Center (TARC), University Medical Center, Johannes Gutenberg University, Hanns-Dieter-Hüsch-Weg 19, Mainz, 55128, Germany;Mouse Behavior Outcome Unit, Focus Program Translational Neurosciences (FTN), Johannes Gutenberg University, Hanns-Dieter-Hüsch-Weg 19, Mainz, 55128, Germany;Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University, Duesbergweg 6, Mainz, 55128, Germany;Institute of Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg University, Langenbeckstrasse 1, Mainz, 55131, Germany

关键词: Embryonic stem cells;    Neural differentiation;    Brain-derived neurotrophic factor;    Spinal cord contusion injury;   

Others  :  1235628
DOI  :  10.1186/s13287-015-0268-x

 received in 2015-09-25, accepted in 2015-12-18,  发布年份 2016

【 摘 要 】

Background

Neural 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.

Methods

Mouse 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.

Results

Motor 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.

Conclusions

The 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.

【 授权许可】

   
2016 Butenschön et al.

【 图 表 】

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